M. Degardin

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.

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.

Short-term health-related quality of life and symptom control with docetaxel, cisplatin, 5-fluorouracil and cisplatin (TPF), 5-fluorouracil (PF) for induction in unresectable locoregionally advanced head and neck cancer patients (EORTC 24971/TAX 323)

Background:The EORTC 24971/TAX 323, a phase III study of 358 patients with unresectable locoregionally advanced squamous cell carcinoma of the head and neck, showed an improved progression-free and overall survival (OS) with less toxicity when docetaxel (T) was added to cisplatin and 5-fluorouracil (PF) for induction and given before radiotherapy (RT). The impact of the addition of docetaxel on patients’ health-related quality of life (HRQOL) and symptoms was investigated.Methods:HRQOL was assessed at baseline, at end of cycle 2, and 4, 6, and 9 months after completion of RT using the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire C30 (QLQ-C30) and the EORTC QLQ Head and Neck Cancer-Specific Module (EORTC QLQ-H&N35). The primary HRQOL scale was global HRQOL per protocol.Results:Compliance to HRQOL assessments was 97% at baseline, but dropped to 54% by 6 months. Data were analysed up to 6 months. There was a trend towards improved global HRQOL during the treatment period. At 6 months after the end of RT, global HRQOL was higher in the TPF arm than in the PF arm, but the low compliance does not allow to draw definitive conclusions. Swallowing and coughing problems decreased more in the TPF arm than in the PF arm at the end of cycle 2, but to a limited extent.Conclusion:Induction chemotherapy with TPF before RT not only improves survival and reduces toxicity compared with PF but also seems to improve global HRQOL in a more sustainable manner.

Treatment of laryngeal cancer: the permanent challenge

There are many options to treat larynx cancers. Throughout the 20th century, surgical research has provided many partial surgery techniques (either open surgery or endoscopic CO2 surgery). In parallel, the modification of radiotherapy schedules has notably improved the local control with definitive irradiation. The appearance of active chemotherapy regimens has also modified the concept of treatment for advanced disease, allowing a decrease in the total indications of laryngectomy, although this remains the treatment of choice in some cases. The selection of the most appropriate treatment is based on a multidisciplinary approach. Early diseases may be treated by open surgery, endoscopic laser CO2 surgery or irradiation. Some advanced diseases may be treated by partial surgery, but the majority are theoretically candidates for radical surgery when resectable. In many instances, but not in all, chemotherapy-based larynx-preserving protocols may avoid performing such mutilating surgery. When inoperable, larynx cancers are better treated by combined chemotherapy and irradiation when the performance status of the patient is compatible with such an intensive regimen.

Evaluation of the impact of tumor HPV status on outcome in patients with locally advanced unresectable head and neck squamous cell carcinoma (HNSCC) receiving cisplatin, 5-fluorouracil with or without docetaxel: a subset analysis of EORTC 24971 study

Background EORTC 24971 was a phase III trial demonstrating superiority of induction regimen TPF (docetaxel, cisplatin, 5-fluorouracil) over PF (cisplatin/5-fluorouracil), in terms of progression-free (PFS) and overall survival (OS) in locoregionally advanced unresectable head and neck squamous cell carcinomas. We conducted a retrospective analysis of prospectively collected data aiming to evaluate whether only HPV(-) patients (pts) benefit from adding docetaxel to PF, in which case deintensifying induction treatment in HPV(+) pts could be considered. Patients and methods Pretherapy tumor biopsies (blocks or slides) were assessed for high-risk HPV by p16 immunohistochemistry, PCR and quantitative PCR. HPV-DNA+ and/or p16+ tumors were subjected to in situ hybridization (ISH) and HPV E6 oncogene expression qRT-PCR analysis. Primary and secondary objectives were to evaluate the value of HPV/p16 status as predictive factor of treatment benefit in terms of PFS and OS. The predictive effect was analyzed based on the model used in the primary analysis of the study with the addition of a treatment by marker interaction term and tested at two-sided 5% significance level. Results Of 358, 119 pts had available tumor samples and 58 of them had oropharyngeal cancer. Median follow-up was 8.7 years. Sixteen of 119 (14%) evaluable samples were p16+ and 20 of 79 (25%) evaluable tumors were HPV-DNA+. 13 of 40 pts (33%) assessed with HPV-DNA ISH and 12 of 28 pts (43%) assessed for HPV E6 mRNA were positive. The preplanned analysis showed no statistical evidence of predictive value of HPV/p16 status for PFS (P = 0.287) or OS (P = 0.118). Conclusions The incidence of HPV positivity was low in the subset of EORTC 24971 pts analyzed. In this analysis only powered to detect a large treatment by marker interaction, there was no statistical evidence that treatment effect found overall was different in magnitude in HPV(+) or HPV(-) pts. These results do not justify selection of TPF versus PF according to HPV status.

996PCETUXIMAB RELATIVE DOSE INTENSITY (RDI) IN RECURRENT/METASTATIC (R/M) SQUAMOUS CELL CARCINOMA OF THE HEAD AND NECK (SCCHN): FIRST OBSERVATIONAL PROSPECTIVE STUDY IN UNSELECTED PATIENTS (DIRECT TRIAL)

ABSTRACT Aim: Cetuximab combined with platinum is the standard first-line therapy in patients (pts) with R/M SCCHN. DIRECT is the first multicenter prospective observational study evaluating cetuximab RDI in this setting. Methods: Pts were prospectively enrolled. No prior systemic therapy for R/M SCCHN was allowed. Pts received cetuximab in combination with platinum, according to the pivotal study EXTREME schedule, 5-FU if not contra-indicated and maintenance treatment with cetuximab every 2 weeks was allowed. The primary endpoint was the number of pts with cetuximab RDI >80%. Results: High quality of data was obtained by frequent monitoring of sites every 3 months (evaluable data in 93% of pts for baseline characteristics and in 89% of pts for cetuximab RDI). 154 pts were enrolled in 53 centres between 2012/11 and 2013/03: 86% male, median age 59 years, 81% with PS 80% in 68.5%, 64.7% and 93%, during chemotherapy (CT), CT + maintenance or maintenance periods respectively. Planned doses of cetuximab were decreased in 9.7% and delayed in 36% of 154 pts, mostly during CT. 97 pts (63.0%) withdrew the study for progression (48.5%), death (31%), toxicity (6%), lost to follow-up (1%), or other reasons (13.5%). Grade > 2 skin toxicities were observed in 9 (5.8%) pts. Conclusions: In unselected pts, RDI data in DIRECT study confirms the feasibility and the good tolerance of cetuximab combined with platinum previously reported in the pivotal trial. DIRECT study supports the use of cetuximab + CT as standard treatment in clinical practice. Disclosure: J. Guigay: Research funding : GSK; Merck Serono; Novartis Honoraria : Merck Serono; B. Petre-Lazar: Medical advisor: Merck Serono; F. Mornex, P. Ceruse, M. Alfonsi and C. Le Tourneau: Honoraria : Merck Serono; A. Berrier: Research funding : Merck Serono; S. Faivre: membership advisory board : Merck Serono Honoraria : Merck Serono Research funding: Merck Serono; F. Rolland: Honoraria : Merck Serono Expert Testimony : Merck Serono. All other authors have declared no conflicts of interest.

Cabazitaxel in recurrent/metastatic squamous cell carcinoma of the head and neck: phase II UNICANCER trial ORL03

Treatments are limited after platinum Cetuximab or anti-PD1 failure for patients with recurrent/metastatic head and neck squamous cell carcinoma. Cabazitaxel has increased overall survival in hormone-refractory metastatic prostate cancer after failure of Docetaxel. Our aim was to detect a signal of activity with Cabazitaxel in patients with head and neck cancer who had failed platinum-, Cetuximab- and taxanes-based chemotherapy. This multicenter phase II trial included progressive patients with an ECOG ≤2. Cabazitaxel was given at 25 mg/m2/3 weeks (maximum of 10 cycles), with growth factors support. Efficacy was centralized and assessed every 6 weeks. The primary endpoint was control rate at six-weeks. A Simon’s two-stage optimal design (P0=0.10; P1=0.30) required 29 evaluable patients. At the end of trial, at least 6 non-progressions were required to consider the drug worthy of further study. Out of the 31 enrolled patients, 29 were eligible; 42% had received at least three previous lines of chemotherapy. For the primary end point, 8 patients (27.6%; 95%CI 12.7%-47.2%) had a stable disease at six weeks. Median progression-free survival was 1.05 months (95%CI 0.69-2.07). All patients were analyzed for toxicity: 6 patients had febrile neutropenia. During the 81 cycles administered, 49 grade 3-5 events were observed concerning 81% of the patients, including 35 severe adverse events of which 15 were related to Cabazitaxel. Although Cabazitaxel met its primary endpoint to deserve further investigations, its toxicity makes it difficult to use in frail patients and new schemes are needed (20 mg/m2 for example) if further investigations are launched.Treatments are limited after platinum Cetuximab or anti-PD1 failure for patients with recurrent/metastatic head and neck squamous cell carcinoma. Cabazitaxel has increased overall survival in hormone-refractory metastatic prostate cancer after failure of Docetaxel. Our aim was to detect a signal of activity with Cabazitaxel in patients with head and neck cancer who had failed platinum-, Cetuximab- and taxanes-based chemotherapy.This multicenter phase II trial included progressive patients with an ECOG ≤2. Cabazitaxel was given at 25 mg/m²/3 weeks (maximum of 10 cycles), with growth factors support. Efficacy was centralized and assessed every 6 weeks. The primary endpoint was control rate at six-weeks. A Simons two-stage optimal design (P0=0.10; P1=0.30) required 29 evaluable patients. At the end of trial, at least 6 non-progressions were required to consider the drug worthy of further study.Out of the 31 enrolled patients, 29 were eligible; 42% had received at least three previous lines of chemotherapy. For the primary end point, 8 patients (27.6%; 95%CI 12.7%-47.2%) had a stable disease at six weeks. Median progression-free survival was 1.05 months (95%CI 0.69-2.07). All patients were analyzed for toxicity: 6 patients had febrile neutropenia.During the 81 cycles administered, 49 grade 3-5 events were observed concerning 81% of the patients, including 35 severe adverse events of which 15 were related to Cabazitaxel.Although Cabazitaxel met its primary endpoint to deserve further investigations, its toxicity makes it difficult to use in frail patients and new schemes are needed (20 mg/m2 for example) if further investigations are launched.

Traitement des carcinomes épidermoïdes localement évolués des voies aéro-digestives supérieures : place de la radio-chimiothérapie

Résumé:La radio-chimiothérapie concomitante est devenue le traitement de référence des carcinomes épidermoïdes localement évolués inopérables de la tête et du cou. L’association d’une chimiothérapie à une radiothérapie hyperfractionnée est également supérieure à une radiothérapie hyperfractionnée exclusive. Par ailleurs la radiochimiothérapie concomitante est actuellement le traitement postopératoire standard des patients à haut risque de récidive locorégionale. Le schéma optimal reste à déterminer. Le cisplatine est la molécule ayant fait la preuve d’une plus grande efficacité et la place de la polychimiothérapie n’est pas encore définie. La toxicité aiguë de ces protocoles nécessite des soins de support adaptés mais la toxicité tardive ne semble pas majorée. Des essais avec un long suivi et une évaluation de la qualité de vie sont nécessaires.Abstract:Concurrent chemoradiotherapy (CRT) has been shown to be superior to radiotherapy (RT) alone in several clinical trials for unresectable head and neck cancer. Additionally, chemotherapy given with hyperfractionated RT leads to improved outcome versus hyperfractionated RT alone. In the postoperative setting, clinical trials suggest that CRT is superior to RT alone in high risk patients. The optimal CRT regimen is still an ongoing study and a matter of debate. In the literature, cisplatin is the most effective drug and the superiority of poly-chemotherapy has not been demonstrated. CRT acute toxicity requires significant supporting care; late toxicity is not increased, but large trials with long follow-up and evaluation of quality of life are needed.