Induction chemotherapy in locally advanced squamous cell carcinoma of the head and neck: role, controversy, and future directions.

Background: The value of induction chemotherapy (ICT) remains under investigation despite decades of research. New advancements in the field, specifically regarding the induction regimen of choice, have reignited interest in this approach for patients with locally advanced squamous cell carcinoma of the head and neck (LA SCCHN). Sufficient evidence has accumulated regarding the benefits and superiority of TPF (docetaxel, cisplatin, and fluorouracil) over the chemotherapy doublet cisplatin and fluorouracil. We therefore sought to collate and interpret the available data and further discuss the considerations for delivering ICT safely and optimally selecting suitable post-ICT regimens. Design: We nonsystematically reviewed published phase III clinical trials on TPF ICT in a variety of LA SCCHN patient populations conducted between 1990 and 2017. Results: TPF may confer survival and organ preservation benefits in a subgroup of patients with functionally inoperable or poor-prognosis LA SCCHN. Additionally, patients with operable disease or good prognosis (who are not candidates for organ preservation) may benefit from TPF induction in terms of reducing local and distant failure rates and facilitating treatment deintensification in selected populations. The safe administration of TPF requires treatment by a multidisciplinary team at an experienced institution. The management of adverse events associated with TPF and post-ICT radiotherapy-based treatment is crucial. Finally, post-ICT chemotherapy alternatives to cisplatin concurrent with radiotherapy (i.e. cetuximab or carboplatin plus radiotherapy) appear promising and must be investigated further. Conclusions: TPF is an evidence-based ICT regimen of choice in LA SCCHN and confers benefits in suitable patients when it is administered safely by an experienced multidisciplinary team and paired with the optimal post-ICT regimen, for which, however, no consensus currently exists.

Long-term update of the 24954 EORTC phase III trial on larynx preservation.

The long-term results of the EORTC 24954 trial comparing sequential versus alternating chemotherapy and radiotherapy (RT) for patients with locally advanced laryngeal and hypopharyngeal cancer are reported. From 1996 to 2004, 450 patients were randomly assigned (1-1) to a sequential arm (SA = induction cisplatin-5fluorouracil followed by a 70Gy-RT for the responders or a total laryngectomy and post-operative RT for the non-responders) and an alternating arm (AA = cisplatin-5fluorouracil alternated with three 2-week courses of 20 Gy-RT for a total dose of 60 Gy). Median follow-up was 10.2 years. Ten-year survival with functional larynx (primary end-point) and overall survival were similar in both arms (18.7% and 33.6% in SA versus 18.3% and 31.6% in AA). Late toxicity was also similar; however, a trend for higher larynx preservation and better laryngeal function was observed in AA.

Best practices in the management of the psycho-oncologic aspects of head and neck cancer patients: recommendations from the European Head and Neck Cancer Society Make Sense Campaign.

Squamous cell carcinoma of the head and neck (SCCHN) is considered a worldwide health care problem. The majority of patients have a history of alcohol abuse and high-level tobacco consumption; however, SCCHN is also associated with exposure to viruses including human papillomavirus (HPV) and Epstein-Barr virus. A major problem facing SCCHN patients is that their disease is often diagnosed at an advanced stage where treatment options may not be curative, or can have severe post-treatment consequences. Confronted with their diagnosis and treatment options, the patient can express a range of emotional reactions which may lead to maladaptive coping. During the SCCHN patient journey, there are a number of stages where emotional support could be offered. A point of contact should be allocated to help patients navigate these stages and deliver practical emotive support (such as encouraging attendance at hospital appointments, compliance with lifestyle modifications and treatment adherence), and to identify if or when more advanced emotive support, in the form of a mental health professional, might be needed. This role might be carried out by a representative within the multidisciplinary health care team (e.g. a nurse). While optimal care is provided by specialist health care professionals, each with specific roles and responsibilities during the patient journey, all are important in screening for emotional distress and providing referral to the mental health team. This article reviews the key points for delivering emotional support to SCCHN patients at each stage of their care. Emotional problems cannot be ignored in SCCHN patients if optimal outcomes are to be achieved, particularly as therapeutic options extend overall survival for many patients. Health care professionals must be able to implement efficient screening for psychological distress to support patient's compliance to their care and treatment. They must also be able to recognize when to refer patients at risk for pharmacological and/or psychotherapeutic interventions.

[Advances in head and neck cancers on behalf of the French Intergroup ORL and GORTEC]. / Évolution des concepts dans les cancers des voies aérodigestives supérieures, sous l'égide de l'Intergroupe ORL (GORTEC, GETTEC, GERCOR).

Head and neck cancers are the fifth among the most common cancers in France. Two thirds of cases occur at an advanced stage. For advanced disease, progression-free survival, despite undeniable progress, remains below 50% at three years. The last 20 years have been marked by the necessity to identify situations where less intense surgery and/or radiotherapy and/or chemotherapy is possible without jeopardizing the prognosis, and situations where a therapeutic intensification is necessary and results in a gain in survival while better preserving function with less toxicity. French cooperative groups gathering radiation oncologists (GORTEC), surgeons (GETTEC) and medical oncologists or physicians involved in the management of systemic treatments in head and neck cancers (GERCOR) are now belonging to the INCa-labelled Intergroup ORL to deal with the challenges of head and neck cancers.

Quality assurance in head and neck surgical oncology: EORTC 24954 trial on larynx preservation.

BACKGROUND: The Head and Neck Cancer Group (HNCG) of the EORTC conducted a quality assurance program in the EORTC 24954 trial on larynx preservation. In this multicentre study, patients with resectable advanced squamous cell carcinoma of the larynx or hypopharynx were randomly assigned for treatment with sequential or alternating chemoradiation. The need for a quality assurance program is the evaluation and prevention of differences in treatments between centres in this multidisciplinary study. METHOD: The surgical subcommittee of the HNCG prepared a questionnaire, and clinical records of all patients were verified during audits of independent teams. Data relating institutional practices were collected during a face to face interview with members of the local team. RESULTS: 271 clinical records from the nine main contributing centres were reviewed. The main difference between centres was the time interval between first consultation and treatment initiation, with a mean of 45 days. On the pathology report the nodal involvement was described by level in 36% of the cases according to the American Academy of Otolaryngology-Head and Neck Surgery classification. Extranodal spread was not always described in neck dissection specimens. CONCLUSION: The EORTC 24954 trial on larynx preservation was the first prospective trial with a quality assurance program in head and neck surgical oncology. The analysis shows similarities in practices, but also points out some important differences between centres. Operation reports were fairly complete, but uniformity in pathology reports should be improved.

Morphologic assessment of mandibular reconstruction by free fibula flap and donor-site functional impairment in a series of 23 patients.

INTRODUCTION: Micro-anastomosed free fibula flap is an attitude of choice in mandibular defect repair in oncology, enabling effective functional rehabilitation. The present study assessed donor and recipient site morphology and donor-site sequelae. PATIENTS AND METHODS: The study consecutively recruited patients undergoing mandibular resection with free fibula flap reconstruction in our centre between December 2003 and September 2008. Assessment on adapted scales was performed by two independent expert physicians and patient self-assessment. RESULTS: Out of 49 mandibular reconstructions performed in the centre over the 5-year study period, 23 patients free of recurrence were included. Satisfaction rates were 73% for the recipient site and 70% for the donor-site, with patient/expert agreement of 47% and 49.5% respectively. Donor-site impact was mainly in terms of reduced ankle range of motion (43% of cases) and flexion strength (39%) and discomfort in running (35%) and walking (26%). Risk factors for dissatisfaction were more than 5% weight loss at admission for recipient site dissatisfaction (patient, P=0.012; expert, P=0.046), and skin graft for donor-site dissatisfaction (patient, P=0.04; expert, P=0.035). CONCLUSION: Free fibula flap was associated with high satisfaction rates, but non-negligible donor-site impact.

Laryngeal preservation with induction chemotherapy for hypopharyngeal squamous cell carcinoma: 10-year results of EORTC trial 24891.

BACKGROUND: We report the 10-year results of the EORTC trial 24891 comparing a larynx-preservation approach to immediate surgery in hypopharynx and lateral epilarynx squamous cell carcinoma. MATERIAL AND METHODS: Two hundred and two patients were randomized to either the surgical approach (total laryngectomy with partial pharyngectomy and neck dissection, followed by irradiation) or to the chemotherapy arm up to three cycles of induction chemotherapy (cisplatin 100 mg/m(2) day 1 + 5-FU 1000 mg/m(2) day 1-5) followed for complete responders by irradiation and otherwise by conventional treatment. The end points were overall survival [OS, noninferiority: hazard ratio (preservation/surgery) ≤ 1.428, one-sided α = 0.05], progression-free survival (PFS) and survival with a functional larynx (SFL). RESULTS: At a median follow-up of 10.5 years on 194 eligible patients, disease evolution was seen in 54 and 49 patients in the surgery and chemotherapy arm, respectively, and 81 and 83 patients had died. The 10-year OS rate was 13.8% in the surgery arm and 13.1% in the chemotherapy arm. The 10-year PFS rates were 8.5% and 10.8%, respectively. In the chemotherapy arm, the 10-year SFL rate was 8.7%. CONCLUSION: This strategy did not compromise disease control or survival (that remained poor) and allowed more than half of the survivors to retain their larynx.

The free vascularized flap and the pectoralis major pedicled flap options: comparative results of reconstruction of the tongue.

Reconstruction after extensive resection of the tongue remains a surgical challenge. Free soft-tissue transfer is now favored for head and neck reconstruction following cancer resection. However, the choice of either free tissue transfer (FTT) or of the pedicled Pectoralis Major Musculocutaneous Flap (PMMF), the workhorse in head and neck reconstruction, remains controversial. The purpose of this study is to assess the post-operative outcomes after radical ablative surgery and reconstruction for patients with a tongue cancer. We conducted a retrospective comparison of two different reconstruction techniques. From January 2000 to December 2006, 70 consecutive patients with tongue cancer had been treated with curative intent by extensive ablative surgery and soft-tissue reconstruction. Sixty percent of tumors were T3 or T4. We compared the post-operative outcomes of both populations: 25 patients underwent FTT and 45 underwent pedicled PMMF. Fifty-seven men and 13 women with a mean age of 55 years constitute the study population. The two groups were comparable in terms of age, gender, and addiction. The choice of flap technique was independent of the ASA scale (p=1.00), the weight of comorbidities (p=0.13), previous radiation therapy (p=0.09), the T-stage (p=0.44) or N-stage (p=0.21). Apart from the rate of flap necrosis, which occurred significantly more often in the PMMF group (p=0.02), post-operative complication rates did not differ between the two groups. The success rate of FTT was 96% (24/25). The duration of the post-operative stay was longer after use of the pedicled flap technique, but the difference did not reach statistical significance (mean duration in days: 23.2 vs. 18.1; p=0.10). Both groups did not differ as regards duration of use of a feeding tube (p=0.84) or of tracheostomy (p=0.54). Local disease-free survival was also similar (p=0.65). The two groups were similar in terms of patients' characteristics. The reliability of free flaps was higher than that of PMMF. The assessment of our practice in the case of extensive tongue defect suggests that reconstruction with free soft-tissue transfer, whenever feasible, should be the first-choice treatment option.

[Locally advanced head and neck cancers: recommendations of an expert panel and perspectives for the use of TPF regimen (docetaxel, cisplatin and fluoro-uracil) as induction therapy]. / Cancers des voies aérodigestives supérieures (VADS) localement avancés: recommandations d'un panel d'experts et de perspectives pour l'utilisation du schéma TPF (docétaxel, cisplatine, 5-fluoro-uracile) en induction.

PURPOSE: The purpose of the present article was to evaluate indications, regimens, treatment modalities, and predictive factors of response to treatment in locally advanced squamous cell carcinoma of the head and neck (SCCHN). METHODS: An expert panel including otolaryngology and head and neck surgery specialists, oncologists, radiotherapists and biologists analyzed the literature providing a synthesis and giving some recommendations. SYNTHESIS: Findings from the main randomized phase III trials highlight that the TPF regimen (docetaxel, cisplatin, fluorouracil) represent a preferential option when induction chemotherapy is indicated in either operable or non-operable patients. Given the potential fragility of patients presenting with SCCHN, treatment modalities in routine use require applying preventive measures and tailored follow-up according to each patient's profile. As regards predictive factors of response to TPF regimen, no factor is currently validated, but ongoing trials should provide better knowledge. CONCLUSION: Progresses in induction chemotherapy have allowed improving the prognosis of patients with locally advanced SCCHN. The TPF regimen represents a major improvement in this indication, and ongoing strategic clinical trials should refine its indications.

[Information on head, neck and lung cancers]. / Cancers des voies aérodigestives supérieures et thoraciques: une vision intégrée.

Notable advances have been achieved in head and neck cancer and in lung cancer as regards oncogenesis knowledge and treatment optimization. Multimodal management including molecular targeted therapies have provided a clear benefit in some circumstances. This review provides information on these two primary sites. Some issues are specific (non-tobacco-related carcinogenesis, antiangogenic agents) while some others are shared by both primary sites (oncogenesis, EGFR pathway targeting). Molecular targeted therapies have shifted some treatment algorithms in head and neck cancer (monoclonal antibodies targeting EGFR and radiotherapy in advanced diseases) and in lung cancer as well (1st line anti VEGFR antibodies, EGFR pathway tyrosin-kinase inhibitors as 2nd line treatment for metastatic diseases). Many new prospects are under evaluation (anti-EGFR antibodies, mTOR inhibitors, multi-targets agents, anti-IGFR1 antibodies). Molecular targeted therapies have also generated new protocols for disease evaluation, imaging and bio-clinical monitoring in order to better select patients and improve the outcome.

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.

[Sensory function of FAMM flap: a report of 15 cases]. / Etude de la sensibilité du lambeau de FAMM : à propos de 15 cas.

INTRODUCTION: The facial artery musculomucosal (FAMM) flap described by Pribaz in 1992 is a musculomucosa flap of the cheek plugged into the higher or lower facial pedicle artery. Indications in terms of substance losses in the oral cavity are numerous. PATIENTS AND METHODS: Twenty cases carried out from 2003 to 2006 at the Oscar-Lambret Neck Surgery Cancer Center are reported with a study first on record, then a study on 15 patients (three deaths, two flaps take away for local recurrence). The dimensions of the flap, its epicritic sensitivity, its sensitivity to hot and cold temperatures, the Semmes-Weinstein test and a key test of pique were analyzed. A neck dissection was most often done in the cases studied, and did not advise against the flap. RESULTS: The main indication was represented by tumors of the floor of the mouth. Individual susceptibility testing were broadly similar to the flap and on the opposite side healthy. The results seem to show that, as with skin flaps, there is a complete recovery of sensation. CONCLUSION: This flap is very reliable and most often resensitizes. The low ligation of the artery during neck dissection does not jeopardize the survival (rich regional anastomoses). The FAMM flap makes up for the loss of medium size substance, it represents a very good solution between directed healing and more consistent skin flaps.

Prognostic factors for adult sarcomas of head and neck.

The optimal management of adult soft-tissue sarcomas is not clearly established. To assess prognostic factors and survival, the experience of 45 recent successive cases was reviewed. Data were collected from a retrospective database (1993-2005) and statistically analyzed. Rhabdomyosarcomas were excluded. The mean age was 50.1 years; there were 24 men and 21 women. The main histological subtypes were undifferentiated sarcoma (14) and angiosarcoma (10); 21 tumours were grade 3 (46%). The most frequent primary sites were neck muscles (15, 33%) and scalp (11, 24%). At presentation, 5 (20%) cases with lymph-node involvement and another 11 cases (24%) with distant metastasis were observed. The treatment was with curative intent in 33 cases (73%). This entailed surgery, with adjuvant radiotherapy in 15 cases and adjuvant chemotherapy in 5 cases. The 5-year overall survival was 52% (+/-8%). In univariate analysis, the poor prognostic factors were high grade, initial metastasis or lymph nodes, absence of surgery, and number of surgical procedures. In multivariate analysis, two factors remained significant: grade (P=0.006) and absence of surgery (P=0.005). After taking into account grade and metastasis at presentation, quality of surgery has prognostic value. The primary aim of a multidisciplinary approach to these tumours must favour complete resection.

Additional direct medical costs associated with nosocomial infections after head and neck cancer surgery: a hospital-perspective analysis.

The clinical impact of surgical site infections (SSI) and postoperative pneumonia (PP) after head and neck cancer surgery has been assessed in the past, but little is known about their economic impact. The present study was designed to evaluate costs related to SSI and PP after head and neck cancer surgery with opening of mucosa. The incidence of SSI and PP was measured in a prospective cohort of 261 patients who had undergone head and neck cancer surgery. The additional direct medical costs related to these infections from the hospital perspective were determined based on postoperative length of stay. The mean direct hospital costs for patients with and without SSI or PP were compared. Of the 261 patients, 81 (31%), 21 (8%) and 13 (5%) developed SSI, PP or both, respectively. The additional lengths of stay attributable to SSI, PP or both were 16, 17 and 31 days, respectively, and additional direct medical costs related to these conditions were 17,000, 19,000 and 35,000 Euros. Nosocomial infections after head and neck cancer surgery significantly increase patients' length of stay and therefore generate additional direct medical costs. These results support the application of preventive interventions to reduce nosocomial infections in this setting.

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).

BACKGROUND: 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. METHODS: Both studies compared the addition of concomitant relatively high doses of cisplatin (on days 1, 22, and 43) to radiotherapy vs radiotherapy alone given after surgery in patients with high-risk cancers of the oral cavity, oropharynx, larynx, or hypopharynx. A comparative analysis of the selection criteria, clinical and pathologic risk factors, and treatment outcomes was carried out using data pooled from these two trials. RESULTS: Extracapsular extension (ECE) and/or microscopically involved surgical margins were the only risk factors for which the impact of CERT was significant in both trials. There was also a trend in favor of CERT in the group of patients who had stage III-IV disease, perineural infiltration, vascular embolisms, and/or clinically enlarged level IV-V lymph nodes secondary to tumors arising in the oral cavity or oropharynx. Patients who had two or more histopathologically involved lymph nodes without ECE as their only risk factor did not seem to benefit from the addition of chemotherapy in this analysis. CONCLUSIONS: Subject to the usual caveats of retrospective subgroup analysis, our data suggest that in locally advanced head and neck cancer, microscopically involved resection margins and extracapsular spread of tumor from neck nodes are the most significant prognostic factors for poor outcome. The addition of concomitant cisplatin to postoperative radiotherapy improves outcome in patients with one or both of these risk factors who are medically fit to receive chemotherapy.

Current clinical outcomes demand new treatment options for SCCHN.

Head and neck cancer can be a devastating disease. The mainstays of treatment for early stage disease are either radiotherapy or surgery. However, although disease responds well at this stage, the risk of a second primary cancer is high, with a development rate of about 4% per year. Advanced diseases are treated either by surgery with postoperative radiotherapy or by definitive radiotherapy, with surgery in reserve for salvage if necessary. Over the past two decades major advances have been made in surgery (reconstructive surgery, non-mutilating surgery). Either definitive or postoperative, radiotherapy is an integral part of the treatment for the majority of non-metastatic stages of disease and ways of improving the effects of radiotherapy are constantly being explored. Good activity has been reported for the use of altered radiation fractionation regimens, which allow the delivery of intensified radiation doses. In addition, in recent years randomized trials and meta-analyses have confirmed the survival benefit of adding chemotherapy to radiotherapy in a number of different settings. Cisplatin-based regimens have been identified as the most active and are now standard treatment choices. The survival benefits of chemotherapy appear to be limited to concomitant administration and do not extend to neoadjuvant administration, although this has demonstrated clinical utility in preserving organ function. Platinum-based combination chemotherapy is by many clinicians considered the standard approach to the treatment of recurrent/metastatic disease for patients who are able to tolerate such regimens, but the prognosis for these patients remains poor; this is particularly true for those whose disease progresses on such therapy. This paper discusses current approaches and recent advances in the treatment of head and neck cancer, specifically squamous cell carcinoma, and suggests future management aims for the different disease stages.