Laryngeal Preservation Strategies in Locally Advanced Laryngeal and Hypopharyngeal Cancers.

For long, the treatment of locoregionally advanced laryngeal and hypopharyngeal squamous cell cancers (SCC) consisted of either total laryngectomy (TL) or definitive radiotherapy (RT). The development of induction cisplatin plus 5-fluorouracil (PF) and the correlation between chemosensitivity and radiosensitivity in previously untreated patients opened a new era of treatment aiming at laryngeal preservation (LP). The fundamental concept was to employ induction PF in order to select patients for subsequent treatment with either TL or RT according to tumor response to PF. The first two trials (VALGSG for laryngeal SCC and EORTC 24891 for hypopharyngeal SCC) concluded that such an approach could preserve nearly 60% of larynx without deleterious impact on survival. The EORTC 24954 trial compared 4 cycles of induction PF followed by RT in good responders vs. alternating PF-RT in laryngeal and hypopharyngeal SCC. There was no significant difference in 5-year overall survival with a functional larynx between the two arms (31 vs. 35%). The GORTEC 2000-01 trial compared induction PF to induction PF plus docetaxel (TPF) both followed by RT in good responders in larynx and hypopharynx SCC. The 5-year LP was significantly higher in the TPF arm (60 vs. 39%) but without a difference in survival. The RTOG 91-11 trial compared induction PF followed by RT in good responders vs. concurrent chemoradiotherapy (chemo-RT) vs. RT alone in laryngeal SCC. There was no significant difference in 5-year laryngectomy-free survival between the patients treated with induction chemotherapy (44%) vs. those treated with chemo-RT (47%), both being superior to RT alone (34%). At 5 years, LP was superior with chemo-RT: 84 vs. 71% with induction PF. Two phase II trials explored the role of cetuximab (E) in LP in laryngeal and hypopharyngeal SCC. The TREMPLIN trial compared RT+E or chemo-RT (RT + P) after TPF. The DeLOS-II trial compared TPE followed by RT+E vs. TP followed by RT. However, these trials failed to indicate an advantage for the incorporation of E in the treatment paradigm. To date, two approaches for LP have been validated: induction TPF followed by RT for laryngeal and hypopharyngeal SCC and concurrent chemo-RT for laryngeal SCC. An ongoing trial (SALTORL) is comparing these two approaches, induction TPF and chemo-RT, in laryngeal/ hypopharyngeal SCC.

Prevalence and characteristics of HPV-driven oropharyngeal cancer in France.

BACKGROUND: France has one of the highest incidence of head and neck cancers in Europe. Despite this, the epidemiological impact of high-risk human papilloma virus (HR-HPV) remains poorly investigated. METHODS: We prospective assessed the proportion of oropharyngeal cancers due to HR-HPV in 15 hospitals throughout France. HPV-status was determined by p16-immunohistochemistry, and by detection of HPV-DNA using in situ hybridization. Cancers were classified as HPV-driven if both p16-immunohistochemistry and HPV-DNA assays were positive. Demographical and clinical features were recorded. RESULTS: 291 patients with palatine-tonsil or tongue-base cancers were recruited from March-2011 to July-2012. Of these, 43.1% of samples were p16-positive and 37.7% were positive for both p16 and HPV-DNA. Prognosis was significantly better in patients with HPV-driven cancers, with smoking negatively impacting patients' oncological outcomes. CONCLUSION: In France, more than a third of tonsillar and tongue base cancers are HPV-driven. More research concerning the evolution of HPV-driven cancers over time is needed.

Determinants of patient delay in doctor consultation in head and neck cancers (Protocol DEREDIA).

INTRODUCTION: Reducing the time between the onset of the first symptoms of cancer and the first consultation with a doctor (patient delay) is essential to improve the vital prognosis and quality of life of patients. Longer patient delay is linked to the already known sociodemographic, socioeconomic, socioeducational, sociocultural and socioprofessional factors. However, recent data suggest that some sociocognitive and emotional determinants may explain patient delay from a complementary point of view. The main objective of this study is to assess whether, in head and neck cancer, patient delay is linked to these sociocognitive and emotional factors, in addition to previously known factors. METHODS AND ANALYSIS: We intend to include in this study 400 patients with a not yet treated head and neck cancer diagnosed in one of six health centres in the North of France region. The main evaluation criterion is 'patient delay'. Sociocognitive, emotional, medical, sociodemographic, socioeconomic, educational, professional and geographic factors will be assessed by means of (1) a case report form, (2) a questionnaire completed by the clinical research associate together with the patient, (3) a questionnaire completed by the patient and (4) a recorded semidirective interview of the patient by a psychologist (for 80 patients only). The collected data will be analysed to underline the differences between patients who consulted a doctor earlier versus those who consulted later. ETHICS: The study has obtained all the relevant authorisations for the protection of patients enrolled in clinical trials (CCTIRS, CCP, CNIL), does not involve products mentioned in article L.5311-1 of the French Code of Public Health, and does not imply any changes in the medical care received by the patients. The study began in October 2012 and will end in June 2015. TRIAL REGISTRATION: ID-RCB 2012-A00005-38.

[Squamous cell carcinoma of the hypopharynx and larynx: evidence-based care]. / Carcinomes épidermoïdes de l'hypopharynx et du larynx : prise en charge fondée sur les preuves.

Squamous cell carcinomas of larynx and hypopharynx can be treated by surgery and/or radiotherapy according to tumor size. For small tumors, the results are similar. For locally advanced tumors, the surgical approach is mutilating and requires a total (pharyngo)laryngectomy. Exclusive chemoradiotherapy has shown its interest at the cost of late sequelae. In order to reduce these effects and mutilation, induction chemotherapy with cisplatin, docetaxel and 5FU for organ preservation becomes the standard treatment but there are no solid studies comparing this approach with the exclusive chemoradiotherapy. And it is not possible to conclude as to the superiority of a scheme in terms of overall survival. When chemotherapy is chosen, the modalities of any potentiation of radiation have not been yet established.

An international phase 3 trial in head and neck cancer: quality of life and symptom results: EORTC 24954 on behalf of the EORTC Head and Neck and the EORTC Radiation Oncology Group.

BACKGROUND: The European Organization for Research and Treatment of Cancer (EORTC) 24954 phase 3 randomized clinical trial compared 2 schemes of combined chemotherapy for patients with resectable cancers of the hypopharynx and larynx: sequential induction chemotherapy and radiotherapy versus alternating chemoradiotherapy. The current study reports detailed effects of both treatment arms on health-related quality of life (HRQOL) and symptoms. METHODS: A total of 450 patients aged 35 years to 76 years (World Health Organization performance status (WHO PS) ≤ 2) with untreated, resectable advanced squamous cell carcinoma of the larynx (tumor classification of T3-T4) or hypopharynx (tumor classification of T2-T3-T4) with regional lymph nodes in the neck classified as N0 to N2 with no metastases were randomized in this prospective phase 3 trial into either the sequential arm (control) or the alternating arm (experimental). QOL assessment was performed at randomization; at baseline; at 42 days; and at 6, 12, 24, 36, and 48 months. RESULTS: There were no observed differences with regard to the primary endpoint of Fatigue and secondary endpoint of Dyspnea. Significant differences were found in the secondary endpoints of Swallowing and Speech problems at 42 days after randomization in favor of patients in the sequential arm. Explanatory and sensitivity analysis revealed that the primary analysis favored the sequential arm, but the majority of differences in HRQOL did not exist at the end of treatment, and returned to baseline levels. CONCLUSIONS: In the current study, a trend toward worse scores was noted in the patients treated on the alternating chemoradiotherapy arm but very few differences reached the level of statistical significance. The HRQOL scores of the majority of patients returned to baseline after therapy.

Sinonasal cancer: Analysis of oncological failures in 156 consecutive cases.

BACKGROUND: Sinonasal cancers are rare and associated with a poor prognosis. The purpose of this study was to report our experience and analyze the risk factors for oncologic failures. METHODS: A retrospective review of 156 consecutive patients treated with curative intent for sinonasal malignancy between 1995 and 2005 at tertiary cancer center was performed. Demographic, clinical, morphological, and pathological parameters were correlated with oncologic outcomes. RESULTS: Complete response was obtained for 134 patients. Sixty-eight patients relapsed, among which 51 had local recurrence. Nine of these 51 patients (17.6%) underwent successful salvage therapy. Five-year local failure and overall survival rates were 50.0% and 61.1%, respectively. Maxillary sinus tumors, intracranial invasion, and N > 0 classification at initial diagnosis were significantly and independently associated with local failure and survival in multivariate analysis. CONCLUSION: Local control after initial treatment is primordial to optimizing outcomes because of the poor results of salvage therapy.

A systematic review of current and emerging approaches in the field of larynx preservation.

Treatment options targeting laryngeal preservation include conservative surgery, concurrent chemo-radiotherapy, induction chemotherapy (IC) followed by radiotherapy (RT), and alternating chemo-radiation. The goal of this paper was to perform a systematic review of randomized clinical trials (RCTs) on current and emerging approaches in the field of larynx preservation. The search identified 36 papers of which 27 did not fall within the inclusion criteria (i.e. non-RCTs). IC followed by RT has been shown to allow laryngeal preservation in about two-thirds of pts with locally advanced laryngeal or hypopharyngeal cancer without compromising survival. IC is regarded as the landmark treatment of non-surgical larynx preservation approaches. Concomitant and alternating chemoradiotherapy treatments are also acceptable in larynx preservation.

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.

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.

Nodal recurrence of sinonasal cancer: does the risk of cervical relapse justify a prophylactic neck treatment?

BACKGROUND: Sinonasal cancers are rare and no high-level evidence exists to determine their optimal management. Prophylactic neck treatment issue remains controversial. The aim of this study was to analyze the pattern of neck failure and to identify any prognostic factors that may influence neck control. METHODS: A retrospective review of 155 consecutive patients treated for sinonasal malignancy, without prophylactic neck treatment, between 1995 and 2005 at tertiary cancer center was performed. Demographic, clinical, morphological and pathological parameters were correlated with oncologic outcomes. RESULTS: Eight out of 155 patients (5%) presented initially with neck node metastasis. Complete remission was obtained for 133 patients after treatment completion. During follow up, 16 out of 133 patients (12%) were affected with regional recurrence. Neck failure occurred in 8 out of 51 patients with local failure and in 8 out of 82 patients locally controlled. Isolated nodal failure was observed in 5 patients initially cN0 out of 133 (3.8%) representing 7.3% of all recurrences and 3 of them underwent successful salvage therapy. None of the tested factors were significantly associated with neck control (p>0.05). Lymph node at diagnosis time was significantly and independently associated with poor survival (p=0.0012). CONCLUSION: Isolated neck relapse, when local control is achieved, is rare and salvage treatment is effective. Routine prophylactic neck treatment has little interest. However, this approach could be profitable to few selected patients, who remain to be defined. Further investigations are needed.

Larynx preservation.

PURPOSE OF REVIEW: Organ preservation, in particular larynx preservation, is a major challenge that has been evaluated during the past 3 decades. This review took in consideration the most recently published articles on this topic. RECENT FINDINGS: There are no new data on this topic but mainly confirming data. Most of the reports underscored that there was still a place for upfront surgery (either partial or total laryngectomy). Nonsurgical approaches are radiotherapy alone or chemotherapy-based protocols with either induction or concomitant chemotherapy added to radiotherapy (with conventional or accelerated fractionation). Different authors underscored that daily practice must follow carefully the selection of patients and monitoring of treatment when applying protocols evaluated in randomized clinical trials. SUMMARY: Larynx preservation is an undisputable advance in larynx cancer management. For early diseases, either surgery (open or endoscopic) or irradiation may control the disease and preserve the larynx function. For advanced cases, chemotherapy-based protocols have been validated, but the best protocol is still to be defined. Importantly some cases still require upfront total laryngectomy. A multidisciplinary approach for decision making is mandatory, whatever the stage.

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.

Larynx preservation: what is the standard treatment?

Locally advanced laryngeal and hypo-pharyngeal cancers have a rather poor prognosis. Up until the early 1990s, standard treatment was total laryngectomy, with dramatic functional and social outcome. The introduction of cisplatin based chemotherapy made concurrent chemo-radiotherapy (CCRT) the standard treatment for selected patients, fit for an organ preservation strategy. Over two decades of improvement in nonsurgical management of locally advanced laryngeal cancer is reviewed, including the most recent improvements with the introduction of taxanes and anti-EGFR targeted therapy.

Functional and sensitive outcomes after tongue reconstruction: about a series of 30 patients.

Few studies reported both functional and sensitive long-term evaluations after tongue reconstruction. The aim of this study was to assess functional outcomes and sensitive recovery after tongue reconstruction with fasciocutaneous free flap (FCFF) or musculocutaneous pedicled flap (MCPF) without nerve anastomosis. We enrolled 30 patients having no recurrence from a consecutive series of 79 tongue reconstructions as part of a cancer treatment. All patients were submitted to functional and sensitive tests. The functional study included intelligibility, tongue motility, food, and swallowing scores. Flap sensibility was evaluated too. Male-to-female sex ratio was 6.5 with a mean age of 52 years old. The lesions were mainly advanced (T3-T4 73%). Mobile tongue and base of tongue resection was carried out in 43% of cases, and resection was limited to the oral tongue for 53%. Twenty-one FCFF and nine MCPF were performed. The mean follow-up was 2 years and 11 months. Swallowing (slightly impaired 63%), food (normal 40%), and intelligibility (excellent 77%) assessments were satisfactory. Spontaneous sensory recovery was regularly observed (mean response 62%). The two groups FCFF and MCPF were similar regarding population and tumors characteristics. Functional results were higher in case of FCFF (food score p=0.05; intelligibility p=0.04). No difference was observed on sensitive recovery. This study emphasizes good functional results either for swallowing or intelligibility, with higher scores for the FCFF, strengthening the opinion that FCFF is the best choice for tongue reconstruction whenever possible.

Induction chemotherapy in head and neck cancer: a new paradigm.

Five hundred and fifty thousand new head and neck cancer cases are diagnosed each year worldwide. They are mostly locally advanced squamous cell carcinoma with a poor prognosis in terms of locoregional and distant failure. A major challenge for patients with locally advanced squamous cell carcinoma is to achieve a high cure rate while preserving functions. Treatment strategies are designed according to the disease stage, primary site, operable status, patient age, and performance status. Surgery, radiation therapy, chemotherapy, and more recently molecular-targeted therapies are part of these strategies, but their sequence remains to be defined. Over the last 30 years, induction chemotherapy has attained an important position in the management of patients with locally advanced squamous cell carcinoma, particularly since the introduction of taxanes. The decision to deliver induction chemotherapy (and its intensification) must be considered in the light of other treatments aiming at better locoregional control (normofractioned radiotherapy, accelerated or hyperfractionated radiotherapy, addition of concurrent chemotherapy, or of targeted therapy) with or without adjuvant treatment. This review summarizes the rationale, these data, and perspectives on induction chemotherapy-based strategies.

Candidates for larynx preservation: the next step?

Nonsurgical treatment approaches to enable larynx preservation in patients who would otherwise undergo laryngectomy have evolved over recent years. Randomized trials have demonstrated that concurrent chemotherapy and radiotherapy is more effective than doublet cisplatin and 5-fluorouracil (5-FU) (PF)-based induction chemotherapy and radiotherapy in enabling larynx preservation. However, concurrent chemotherapy and radiotherapy is also associated with more toxicities than induction PF followed by radiotherapy. The triplet induction regimen of docetaxel, cisplatin, and 5-FU (TPF) is more effective than PF and is now considered to be the standard induction chemotherapy regimen for future larynx preservation trials. Manipulating the postinduction treatment regimen may help to improve larynx preservation rates, and possibly survival, and the use of concurrent chemoradiotherapy and radiotherapy plus the epidermal growth factor receptor inhibitor cetuximab has been investigated in this setting. Determining the most effective treatment approach for larynx preservation will involve conducting a trial comparing concurrent chemotherapy and radiotherapy with sequential TPF induction chemotherapy followed by either radiotherapy or cetuximab plus radiotherapy. Collaboration among international groups is required to assess which approach would be most beneficial in terms of larynx function preservation, disease control, and survival.

Cetuximab in the management of locoregionally advanced head and neck cancer: expanding the treatment options?

The treatment of locoregionally advanced squamous cell carcinoma of the head and neck (SCCHN) has evolved in recent years as a consequence of a better understanding of the potential benefits associated with altered radiation fractionation regimens, concurrently administered chemotherapy and radiotherapy (chemoradiotherapy) and induction chemotherapy. Concurrent chemoradiotherapy is a treatment option for technically resectable disease, where functional morbidity precludes the use of surgery. Induction chemotherapy followed by radiotherapy may also be used in this setting, and has been validated for larynx preservation. Concurrent chemoradiotherapy is a standard treatment approach for medically fit patients with locoregionally advanced unresectable disease. However, the toxicity burden of additional chemotherapy in both the concurrent chemoradiotherapy and induction chemotherapy settings can have implications for treatment compliance and may impede the administration of chemotherapy and/or radiotherapy to schedule. The epidermal growth factor receptor (EGFR)-targeted IgG1 monoclonal antibody, cetuximab (Erbitux), has shown significant clinical benefits in the treatment of both locoregionally advanced and recurrent and/or metastatic SCCHN. A phase III study in locoregionally advanced disease demonstrated significant improvements in locoregional control and progression-free and overall survival with cetuximab plus radiotherapy compared with radiotherapy alone, and overall survival benefits were maintained at 5 years. The addition of cetuximab to concurrent chemoradiotherapy has been shown to be feasible in phase II trials and is being investigated in phase III trials. Preliminary evidence suggests that cetuximab could be incorporated into induction management strategies. Taken together, these data support an important role for cetuximab in the treatment paradigm for locoregionally advanced SCCHN.