Jean-Louis Lefebvre

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)

In 2004, level I evidence was established for the postoperative adjuvant treatment of patients with selected high‐risk locally advanced head and neck cancers, with the publication of the results of two trials conducted in Europe (European Organization Research and Treatment of Cancer; EORTC) and the United States (Radiation Therapy Oncology Group; RTOG). Adjuvant chemotherapy‐enhanced radiation therapy (CERT) was shown to be more efficacious than postoperative radiotherapy for these tumors in terms of locoregional control and disease‐free survival. However, additional studies were needed to identify precisely which patients were most suitable for such intense treatment.

Induction Chemotherapy Followed by Either Chemoradiotherapy or Bioradiotherapy for Larynx Preservation: The TREMPLIN Randomized Phase II Study

PURPOSE To compare the efficacy and safety of induction chemotherapy (ICT) followed by chemoradiotherapy (CRT) or bioradiotherapy (BRT) for larynx preservation (LP). PATIENTS AND METHODS Previously untreated patients with stage III to IV larynx/hypopharynx squamous cell carcinoma received three cycles of ICT-docetaxel and cisplatin 75 mg/m(2) each on day 1 and fluorouracil 750 mg/m(2) per day on days 1 through 5. Poor responders (< 50% response) underwent salvage surgery. Responders (≥ 50% response) were randomly assigned to conventional radiotherapy (RT; 70 Gy) with concurrent cisplatin 100 mg/m(2) per day on days 1, 22, and 43 of RT (arm A) or concurrent cetuximab 400 mg/m(2) loading dose and 250 mg/m(2) per week during RT (arm B). Primary end point was LP at 3 months. Secondary end points were larynx function preservation (LFP) and overall survival (OS) at 18 months. RESULTS Of the 153 enrolled patients, 116 were randomly assigned after ICT (60, arm A; 56, arm B). Overall toxicity of both CRT and BRT was substantial following ICT. However, treatment compliance was higher in the BRT arm. In an intent-to-treat analysis, there was no significant difference in LP at 3 months between arms A and B (95% and 93%, respectively), LFP (87% and 82%, respectively), and OS at 18 months (92% and 89%, respectively). There were fewer local treatment failures in arm A than in arm B; salvage surgery was feasible in arm B only. CONCLUSION There is no evidence that one treatment was superior to the other or could improve the outcome reported with ICT followed by RT alone (French Groupe Oncologie Radiothérapie Tête et Cou [GORTEC] 2000-01 trial [Induction CT by Cisplatin, 5FU With or Without Docetaxel in Patients With T3 and T4 Larynx and Hypopharynx Carcinoma]). The protocol that can best compare with RT alone after ICT is still to be determined.

Phase 3 Randomized Trial on Larynx Preservation Comparing Sequential vs Alternating Chemotherapy and Radiotherapy

BACKGROUND Both induction chemotherapy followed by irradiation and concurrent chemotherapy and radiotherapy have been reported as valuable alternatives to total laryngectomy in patients with advanced larynx or hypopharynx cancer. We report results of the randomized phase 3 trial 24954 from the European Organization for Research and Treatment of Cancer. METHODS Patients with resectable advanced squamous cell carcinoma of the larynx (tumor stage T3-T4) or hypopharynx (T2-T4), with regional lymph nodes in the neck staged as N0-N2 and with no metastasis, were randomly assigned to treatment in the sequential (or control) or the alternating (or experimental) arm. In the sequential arm, patients with a 50% or more reduction in primary tumor size after two cycles of cisplatin and 5-fluorouracil received another two cycles, followed by radiotherapy (70 Gy total). In the alternating arm, a total of four cycles of cisplatin and 5-fluorouracil (in weeks 1, 4, 7, and 10) were alternated with radiotherapy with 20 Gy during the three 2-week intervals between chemotherapy cycles (60 Gy total). All nonresponders underwent salvage surgery and postoperative radiotherapy. The Kaplan-Meier method was used to obtain time-to-event data. RESULTS The 450 patients were randomly assigned to treatment (224 to the sequential arm and 226 to the alternating arm). Median follow-up was 6.5 years. Survival with a functional larynx was similar in sequential and alternating arms (hazard ratio of death and/or event = 0.85, 95% confidence interval = 0.68 to 1.06), as were median overall survival (4.4 and 5.1 years, respectively) and median progression-free interval (3.0 and 3.1 years, respectively). Grade 3 or 4 mucositis occurred in 64 (32%) of the 200 patients in the sequential arm who received radiotherapy and in 47 (21%) of the 220 patients in the alternating arm. Late severe edema and/or fibrosis was observed in 32 (16%) patients in the sequential arm and in 25 (11%) in the alternating arm. CONCLUSIONS Larynx preservation, progression-free interval, and overall survival were similar in both arms, as were acute and late toxic effects.

Randomized trial of induction chemotherapy in larynx carcinoma

We conducted a randomized study in patients with previously untreated advanced (T3) larynx carcinoma to compare total laryngectomy followed by radiotherapy to induction chemotherapy, followed by radiotherapy in good responders, and by total laryngectomy plus radiotherapy in poor responders. A total of 68 patients were included in the study, 36 in the induction chemotherapy group and 32 in the no chemotherapy group. 15 of the 36 patients in the induction chemotherapy group did not have a laryngectomy. Survival and disease-free survival were significantly worse in the induction chemotherapy group than in the no chemotherapy group (P = 0.006 and P = 0.02, respectively). The 2-year survival rates were 69% in the induction chemotherapy group and 84% in the no chemotherapy group. Larynx preservation for patients, selected on the basis of having responded to induction chemotherapy, cannot be considered a standard treatment at the present time.

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

PURPOSE 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. RESULTS 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 beta-catenin, epiregulin and amphiregulin, and TP53 mutation. CONCLUSIONS 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.

Cancer of the larynx.

Abstract In Europe, laryngeal cancer accounts for only 2–5% of all cancers, the incidence being much higher among males than among females. Smoke and alcohol represent the major behavioural risk factors. Several carcinogens, occupations and vitamin deficiencies have been associated with laryngeal cancer. A genetic susceptibility to environmental risk factors and carcinogens is recognized. Hoarseness is the main symptom for which patients call for medical consultation. Mucosa is the most common histologic site of the primary lesions considered in the present chapter. Nodal involvement, the site and volume of the primary tumour, and some genes expression represent the major prognostic factors. A high death rate for not cancer-related events is to be pointed out. The loco-regional extent of the disease determines the success of cure. Surgery and radiotherapy represent the main therapeutic options. The choice between these two procedures is often controversial.

Cervical lymph nodes from an unknown primary tumor in 190 patients

Over 10 years, 475 patients with isolated lateral neck masses were evaluated: 190 with lymph nodes from an unknown primary tumor (LNUP), 188 with neck lymphomas, 78 with benign tumors, 10 with sarcomas, and 9 with chemodectomas. This study focused on the patients with LNUP. Only 86 patients were treated with surgery (plus radiotherapy). Other patients were treated with radiotherapy (84) or chemotherapy (13) or had no treatment (7). For the overall population, failures in the neck occurred in 51% of the patients and distant metastases in 27%, while primary tumors appeared in 16%. Survival rates at 3, 5, and 10 years were 27%, 19%, and 7%, respectively, for the overall population and 45%, 35%, and 19%, respectively, for the surgical group. The diagnosis and therapeutic approach had a direct effect on neck control; failure in the neck occurred in 7 of 47 patients (15%) when fine needle aspiration and radical neck dissection with radiotherapy were performed, in 5 of 12 patients (42%) when fine needle aspiration and modified neck dissection with radiotherapy were used, in 5 of 12 patients (42%) when adenectomy diagnosis and radiotherapy treatment were performed, and in 6 of 11 patients (54%) when diagnosis by incisional biopsy was performed prior to admission, despite subsequent radical neck dissection and radiotherapy treatment. In our opinion, panendoscopy and fine needle aspiration should be the first-line diagnostic approach. When cytologic diagnosis proves impossible, the second-line approach must consist of cervical exploration with frozen section examination and excisional biopsy, followed by immediate appropriate treatment. In cases of LNUP, radical neck dissection seems to be preferable.

Cancer of the oropharynx

Oropharyngeal cancer is a rare tumour. Tobacco use and alcohol consumption are recognised as major risk factors. Several carcinogens, occupational exposures and vitamin deficiencies represent the most significant predisposing factors. A varying host susceptibility to carcinogens can be inferred. Carcinoma of the oropharynx has to be suspected whenever sore throat, odynophagia, and ear-ache are described by the patient. Biopsy is mandatory for the definitive diagnosis. TNM classification is crucial for treatment decision-making, while stage grouping is less important. Prognostic factors are treatment-related. Standard treatment of T1-T2 tumours is radiation therapy, for T3 and T4 tumour treatment options are controversial. More advanced tumours can be treated either with surgery followed by conventional radiotherapy or by combined chemo-radiation. Non-conventional fractionation radiotherapy in combination with chemotherapy may represent a third option. Acute toxicity needs to be managed promptly. Late sequelae are less known. Treatment of such tumours requires a multidisciplinary approach within experienced centres.

Multi institutional phase II study of concomitant stereotactic reirradiation and cetuximab for recurrent head and neck cancer.

PURPOSE Recurrent head and neck cancer is associated to a poor survival prognosis. A high toxicity rate is demonstrated when surgery and/or radiotherapy and/or chemotherapy are combined. Furthermore, the duration of treatment is often not ethically compatible with the expected survival (median survival<1year). Normal tissues tolerance limits the use of reirradiation and stereotactic body radiotherapy (SBRT) could offer precise irradiation while sparing healthy tissues. After completion of a feasibility study, results of a multicentric study (Lille, Nancy & Nice) using SBRT with cetuximab are reported. The aim of the study was to deliver non toxic short course SBRT (2weeks) in order to get the same local control as the one demonstrated with longer protocols. METHODS AND MATERIALS Patients with inoperable recurrent, or new primary tumor in a previously irradiated area, were included (WHO<3). Reirradiation (RT) dose was 36Gy in six fractions of 6Gy to the 85% isodose line covering 95% of the PTV with 5 injections of concomitant cetuximab (CT). All patients had previous radiotherapy, 85% had previous surgery and 48% previous chemotherapy. RESULTS Between 11/2007 and 08/2010, 60 were included (46 men and 14 women), 56 received CT+RT, 3 were not treated and 1 received only CT. Median age was 60 (42-87)) and all 56 patients had squamous carcinoma and received concomitant cetuximab. Mean time between previous radiotherapy and the start of SBRT was 38months. Cutaneous toxicity was observed for 41 patients. There was one toxic death from hemorrhage and denutrition. Median follow-up was 11.4months. At 3months, response rate was 58.4% (95% CI: 43.2-72.4%) and disease control rate was 91.7% (95% CI: 80.0-97.7%). The one-year OS rate was 47.5% (95% CI: 30.8-62.4). CONCLUSION These results suggest that short SBRT with cetuximab is an effective salvage treatment with good response rate in this poor prognosis population with previously irradiated HNC. Treatment is feasible and, with appropriate care to limiting critical structure, acute toxicities are acceptable. This combination may be the reference treatment is this population.

Salvage Stereotactic Reirradiation With or Without Cetuximab for Locally Recurrent Head-and-Neck Cancer: A Feasibility Study

PURPOSE Normal tissues tolerance limits the use of reirradiation for recurrent head-and-neck cancers (HNC). Stereotactic body radiotherapy (SBRT) could offer precise irradiation while sparing healthy tissues. Results of a feasibility study using SBRT with or without cetuximab are reported for reirradiation of recurrent primary HNC. METHODS AND MATERIALS Patients with inoperable recurrent, or new primary tumor, in a previously irradiated area were included. Reirradiation dose was 36 Gy in six fractions of 6 Gy to the 85% isodose line covering 95% of the planning target volume. Patients with squamous cell carcinoma received concomitant cetuximab. RESULTS Between June 2007 and January 2010, 40 patients were prospectively treated for 43 lesions. Median age was 60 and median tumor size was 29 mm. Fifteen patients received concomitant cetuximab and 1 received concomitant cisplatin. Median follow-up was 25.6 months with 34 patients evaluable for tumor response. Median overall survival was 13.6 months and response rate was 79.4% (15 complete and 12 partial responses). Grade 3 toxicity occurred in 4 patients. CONCLUSION These results suggest that short SBRT with or without cetuximab is an effective salvage treatment with good response rate in this poor prognosis population with previously irradiated HNC. Treatment is feasible and, with appropriate care to limiting critical structure, acute toxicities are acceptable. A prospective multicenter Phase II trial of SRT and concomitant cetuximab in recurrent HNC squamous cell carcinoma is ongoing.