Larynx Preservation Clinical Trial Design: Key Issues and Recommendations—A Consensus Panel Summary


      To develop guidelines for the conduct of Phase III clinical trials of larynx preservation in patients with locally advanced laryngeal and hypopharyngeal cancer.

      Methods and Materials

      A multidisciplinary international consensus panel developed recommendations after reviewing results from completed Phase III randomized trials, meta-analyses, and published clinical reports with updates available through November, 2007. The guidelines were reviewed and approved by the panel.


      According to the recommendations, the trial population should include patients with T2 or T3 laryngeal or hypopharyngeal squamous cell carcinoma not considered for partial laryngectomy and exclude those with laryngeal dysfunction or age greater than 70 years. Functional assessments should include speech and swallowing. Voice should be routinely assessed with a simple, validated instrument. The primary endpoint should capture survival and function. The panel created a new endpoint: laryngo-esophageal dysfunction–free survival. Events are death, local relapse, total or partial laryngectomy, tracheotomy at 2 years or later, or feeding tube at 2 years or later. Recommended secondary endpoints are overall survival, progression-free survival, locoregional control, time to tracheotomy, time to laryngectomy, time to discontinuation of feeding tube, and quality of life/patient-reported outcomes. Correlative biomarker studies for near-term trials should include estimated glomerular filtration rate, excision repair cross-complementary-1 gene, E-cadherin and β-catenin, epiregulin and amphiregulin, and TP53 mutation.


      Revised trial designs in several key areas are needed to advance the study of larynx preservation. With consistent methodologies, clinical trials can more effectively evaluate and quantify the therapeutic benefit of novel treatment options for patients with locally advanced laryngeal and hypopharyngeal cancer.
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        • VALCSG (The Department of Veterans Affairs Laryngeal Cancer Study Group)
        Induction chemotherapy plus radiation compared with surgery plus radiation in patients with advanced laryngeal cancer.
        N Engl J Med. 1991; 324: 1685-1690
        • Lefebvre J.-L.
        • Chevalier D.
        • Luboinski B.
        • et al.
        Larynx preservation in pyriform sinus cancer: Preliminary results of a European Organization for Research and Treatment of Cancer phase III trial.
        J Natl Cancer Inst. 1996; 88: 890-899
        • Forastiere A.A.
        • Goepfert H.
        • Maor M.
        • et al.
        Concurrent chemotherapy and radiotherapy for organ preservation in advanced laryngeal cancer.
        N Engl J Med. 2003; 349: 2091-2098
        • Forastiere A.A.
        • Maor M.
        • Weber R.S.
        • et al.
        Long-term results of Intergroup RTOG 91-11: A phase III trial to preserve the larynx—induction cisplatin/5-FU and radiation therapy vs. concurrent cisplatin and radiation therapy vs. radiation therapy.
        J Clin Oncol 2006. 2006; 24 ([ASCO Annual Meeting Proc Part I, abstract]): 5517
        • Marur S.
        • Forastiere A.A.
        Head and neck cancer: Changing epidemiology, diagnosis, and treatment.
        Mayo Clin Proc. 2008; 83: 489-501
        • Posner M.R.
        • Hershock D.M.
        • Blajman C.R.
        • et al.
        Cisplatin and fluorouracil alone or with docetaxel in head and neck cancer.
        N Engl J Med. 2007; 357: 1705-1715
        • Bonner J.A.
        • Harari P.M.
        • Giralt J.
        • et al.
        Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck.
        N Engl J Med. 2006; 354: 567-578
        • Urba S.
        • Wolf G.
        • Eisbruch A.
        • et al.
        Single-cycle induction chemotherapy selects patients with advanced laryngeal cancer for combined chemoradiation: A new treatment paradigm.
        J Clin Oncol. 2006; 24: 593-598
        • Weber R.S.
        • Berkey B.A.
        • Forastiere A.
        • et al.
        Outcome of salvage total laryngectomy following organ preservation therapy: The Radiation Therapy Oncology Group trial 91-11.
        Arch Otolaryngol Head Neck Surg. 2003; 129: 44-49
        • Spaulding M.B.
        • Fischer S.G.
        • Wolf G.T.
        • et al.
        Tumor response, toxicity, and survival after neoadjuvant organ-preserving chemotherapy for advanced laryngeal carcinoma.
        J Clin Oncol. 1994; 12: 1592-1599
        • Bradford C.R.
        • Wolf G.T.
        • Carey T.E.
        • et al.
        Predictive markers for response to chemotherapy, organ preservation, and survival in patients with advanced laryngeal carcinoma.
        Otolaryngol Head Neck Surg. 1999; 121: 534-538
        • Lefebvre J.-L.
        • Chevalier D.
        • Luboinski B.
        • et al.
        Is laryngeal preservation (LP) with induction chemotherapy (ICT) safe in the treatment of hypopharyngeal SCC? Final results of the EORTC 24891 trial.
        J Clin Oncol. 2004; 22 ([ASCO Annual Meeting Proc (Post-Meeting Edition, abstract]): 5531
        • Richard J.M.
        • Sancho-Garnier H.
        • Pessey J.J.
        • et al.
        Randomized trial of induction chemotherapy in larynx carcinoma.
        Oral Oncol. 1998; 34: 224-228
        • Calais G.
        • Pointreau Y.
        • Alfonsi M.
        • et al.
        Induction chemotherapy for larynx preservation. Updated results of the GORTEC 2000-01 randomized trial comparing docetaxel + cisplatinum + fluorouracil (TPF) vs. cisplatinum + fluorouracil (PF).
        Eur J Cancer. 2007; 5 ([Abstract]): 324
        • Lefebvre J.
        • Horiot J.
        • Rolland F.
        • et al.
        Phase III study on larynx preservation comparing induction chemotherapy and radiotherapy vs. alternating chemoradiotherapy in resectable hypopharynx and larynx cancers. EORTC protocol 24954-22950.
        J Clin Oncol. 2007; 25 ([ASCO Annual Meeting Proc Part I, abstract]): LBA6016
        • Bernier J.
        • Cooper J.S.
        • Pajak T.F.
        • et al.
        Defining risk levels in locally advanced head and neck cancers: A comparative analysis of concurrent postoperative radiation plus chemotherapy trials of the EORTC (#22931) and RTOG (#9501).
        Head Neck. 2005; 27: 843-850
        • Brockstein B.
        • Haraf D.J.
        • Rademaker A.W.
        • et al.
        Patterns of failure, prognostic factors and survival in locoregionally advanced head and neck cancer treated with concomitant chemoradiotherapy: A 9-year, 337-patient, multi-institutional experience.
        Ann Oncol. 2004; 15: 1179-1186
        • Li X.M.
        • Wei W.I.
        • Guo X.F.
        • et al.
        Cervical lymph node metastatic patterns of squamous carcinomas of the upper aerodigestive tract.
        J Laryngol Otol. 1996; 110: 937-941
        • Mendenhall W.M.
        • Parsons J.T.
        • Stringer S.P.
        • et al.
        Stage T3 squamous cell carcinoma of the glottic larynx: A comparison of laryngectomy and irradiation.
        Int J Radiat Oncol Biol Phys. 1992; 23: 725-732
        • MacKenzie R.
        • Franssen E.
        • Balogh J.
        • et al.
        The prognostic significance of tracheostomy in carcinoma of the larynx treated with radiotherapy and surgery for salvage.
        Int J Radiation Oncology Biol Phys. 1998; 41: 43-51
        • Pignon J.P.
        • Bourhis J.
        • Domenge C.
        • et al.
        Chemotherapy added to locoregional treatment for head and neck squamous-cell carcinoma: Three meta-analyses of updated individual data.
        Lancet. 2000; 355: 949-955
        • Lefebvre J.-L.
        • Buisett E.
        • Coche-Dequeant B.
        • et al.
        Epilarynx: Pharynx or larynx?.
        Head Neck. 1995; 17: 377-781
        • Eisbruch A.
        • Thornton A.F.
        • Urba S.
        • et al.
        Chemotherapy followed by accelerated fractionated radiation for larynx preservation in patients with advanced laryngeal cancer.
        J Clin Oncol. 1996; 14: 2322-2330
        • Machtay M.
        • Moughan J.
        • Trotti A.
        • et al.
        Pre-treatment and treatment related risk factors for severe late toxicity after chemo-RT for head and neck cancer: An RTOG analysis.
        J Clin Oncol. 2006; 24 ([ASCO Annual Meeting Proc Part I, abstract]): 5500
        • Rosen C.A.
        • Lee A.S.
        • Osborne J.
        • et al.
        Development and validation of the voice handicap index-10.
        Laryngoscope. 2004; 114: 1549-1556
        • Hogikyan N.D.
        • Sethuraman G.
        Validation of an instrument to measure voice-related quality of life (V-RQOL).
        J Voice. 1999; 13: 557-569
        • Fung K.
        • Lyden T.H.
        • Lee J.
        • et al.
        Voice and swallowing outcomes of an organ-preservation trial for advanced laryngeal cancer.
        Int J Radiat Oncol Biol Phys. 2005; 63: 1395-1399
        • List M.A.
        • Rutherford J.L.
        • Stracks J.
        • et al.
        Prioritizing treatment outcomes: Head and neck cancer patients vs. nonpatients.
        Head Neck. 2004; 26: 163-170
        • Ronis D.L.
        • Duffy S.A.
        • Fowler K.E.
        • et al.
        Changes in quality of life over 1 year in patients with head and neck cancer.
        Arch Otolaryngol Head Neck Surg. 2008; 134: 241-248
        • Terrell J.E.
        • Ronis D.L.
        • Fowler K.E.
        • et al.
        Clinical predictors of quality of life in patients with head and neck cancer.
        Arch Otolaryngol Head Neck Surg. 2004; 130: 401-408
        • Hoffman H.T.
        • Porter K.
        • Karnell L.H.
        • et al.
        Laryngeal cancer in the United States: Changes in demographics, patterns of care, and survival.
        Laryngoscope. 2006; 116: 1-13
        • Grandis J.R.
        • Melhem M.F.
        • Gooding W.E.
        • et al.
        Levels of TGF-alpha and EGFR protein in head and neck squamous cell carcinoma and patient survival.
        J Natl Cancer Inst. 1998; 90: 824-832
        • Ang K.K.
        • Berkey B.A.
        • Tu X.
        • et al.
        Impact of epidermal growth factor receptor expression on survival and pattern of relapse in patients with advanced head and neck carcinoma.
        Cancer Res. 2002; 62: 7350-7356
        • Sok J.C.
        • Coppelli F.M.
        • Thomas S.M.
        • et al.
        Mutant epidermal growth factor receptor (EGFRvIII) contributes to head and neck cancer growth and resistance to EGFR targeting.
        Clin Cancer Res. 2006; 12: 5064-5073
        • Mountzios G.
        • Handra-Luca A.
        • Hernandez J.
        • et al.
        ERCC1 immunohistochemical expression and cancer-specific survival in patients with locally advanced squamous-cell carcinoma of the head and neck treated by cisplatin-based induction chemotherapy.
        J Clin Oncol. 2007; 25 ([ASCO Annual Meeting Proc Part I, abstract]): 6011
        • El-Naggar A.K.
        • Lippman S.M.
        • Johnson F.M.
        • et al.
        Correlation of Src activation with epithelial-mesenchymal transformation and aggressive features of head and neck squamous carcinoma.
        J Clin Oncol. 2007; 25 ([ASCO Annual Meeting Proc Part I, abstract]): 6026
        • Khambata-Ford S.
        • Garrett C.R.
        • Meropol N.J.
        • et al.
        Expression of epiregulin and amphiregulin and K-ras mutation status predict disease control in metastatic colorectal cancer patients treated with cetuximab.
        J Clin Oncol. 2007; 25: 3230-3237
        • Poeta M.L.
        • Manola J.
        • Goldwasser M.A.
        • et al.
        TP53 mutations and survival in squamous-cell carcinoma of the head and neck.
        N Engl J Med. 2007; 357: 2552-2561
        • Rosenbek J.C.
        • Robbins J.A.
        • Roecker E.B.
        • et al.
        A penetration–aspiration scale.
        Dysphagia. 1996; 11: 93-98
        • Rademaker A.W.
        • Pauloski B.F.
        Oropharyngeal swallow efficiency as a representative measure of swallowing function.
        J Speech Hearing Res. 1994; 37: 314-325
      1. Ludlow, CL, Sonies, BC, Humbert IA, et al. Validity and reliability of the Swallowing Safety Scale. Poster presentation at The Fifteenth Annual Dysphagia Research Society Meeting, March 8–10, 2007. Poster #59; Conference book p 362.

        • List M.A.
        • Ritter-Sterr C.
        • Lansky S.B.
        A performance status scale for head and neck cancer patients.
        Cancer. 1990; 66: 564-569
        • Chen A.Y.
        • Frankowski R.
        • Bishop-Leone J.
        • et al.
        The development and validation of a dysphagia-specific quality-of-life questionnaire for patients with head and neck cancer: The M.D. Anderson Dysphagia Inventory.
        Arch Otolaryngol Head Neck Surg. 2001; 127: 870-876
        • Karnell M.
        • Melton J.
        • Childes T.
        • et al.
        Reliability of clinician-based (GRBAS and CAPE-V) and patient-based (V-RQOL and IPVI) documentation of voice disorders.
        J Voice. 2007; 21: 576-590
        • Rosenthal D.I.
        • Mendoza T.R.
        • Chambers M.S.
        • et al.
        Measuring head and neck cancer symptom burden: The development and validation of the M.D. Anderson Symptom Inventory, head and neck module.
        Head Neck. 2007; 29: 923-931
        • Bjordal K.
        • Hammerlid E.
        • Ahlnder-Elmqvist M.
        • et al.
        Quality of life in head and neck cancer patients: Validation of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire–H&N35.
        J Clin Oncol. 1999; 17: 1008-1019
        • Op de Coul B.M.
        • Ackerstaff A.H.
        • van As C.J.
        • et al.
        Quality of life assessment in laryngectomized individuals: Do we need additions to standard questionnaires in specific clinical research projects?.
        Clin Otolaryngol. 2005; 30: 169-175


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