Long-term outcomes and safety after reirradiation in locally recurrent nasopharyngeal carcinoma in a non-endemic area.

PURPOSE: To determine outcomes and toxicities after reirradiation for locally recurrent nasopharyngeal carcinoma (rNPC) and to apply a prognostic index in a non-endemic region. METHODS: We retrospectively reported progression-free survival (PFS), overall survival (OS), and treatment-related toxicities in patients treated with curative intent for locally rNPC. We applied the prognostic model for OS and grade 5 radiotherapy (RT)-related toxicities published by Li et al. and evaluated its prognostic accuracy by receiver operating characteristic (ROC) curve analysis. RESULTS: Between 2005 and 2018, 33 patients were treated for rNPC in our institution. Median follow-up was 60 months. The mean time to local recurrence was 75 months. Six (18%) patients had a persistent grade 3 toxicity from a previous RT course. The median re-RT dose was 66 Gy. After re-RT, 13 patients had local failure and 3 patients had metastatic recurrence. Median PFS was 18 months with a 5-year PFS rate of 29%. Median OS was 35 months with a 5-year OS rate of 37%. Grade 3 or higher toxicities rate was 74%. There were 21% grade 5 toxicities. The median time to a grade 5 toxicity was less than 6 months following re-RT. The prognostic nomogram was not predictive for OS or grade 5 toxicities. CONCLUSION: Reirradiation of rNPC is an effective treatment but is associated with a high rate of life-threatening toxicity. Stratification of patients based on their risk of developing severe toxicity is needed to select patients who will most likely benefit from re-RT.

The anterolateral thigh perforator flap in pharyngo-esophageal reconstruction.

Today's customary techniques for pharyngo-esophageal reconstruction are jejunum and radial forearm free flaps. In this type of reconstruction, the jejunum flap is considered as the reference, but when its harvesting is not possible, the radial forearm flap is used. Since perforator flaps have begun to be developed, the anterolateral thigh flap (ATF) has become increasingly prominent in pharyngo-esophageal reconstruction. The aim of our study was to describe the use of the anterolateral perforator flap in pharyngo-esophageal reconstruction (indications, harvesting method, flap design) and to discuss its advantages and drawbacks as regards oral feeding and esophageal speech.

An exploratory, open-label, randomized, multicenter study to investigate the pharmacodynamics of a glycoengineered antibody (imgatuzumab) and cetuximab in patients with operable head and neck squamous cell carcinoma.

BACKGROUND: In addition to inhibiting epidermal growth factor receptor (EGFR) signaling, anti-EGFR antibodies of the IgG1 'subtype' can induce a complementary therapeutic effect through the induction of antibody-dependent cell-mediated cytotoxicity (ADCC). Glycoengineering of therapeutic antibodies increases the affinity for the Fc-gamma receptor, thereby enhancing ADCC. PATIENTS AND METHODS: We investigated the changes in immune effector cells and EGFR pathway biomarkers in 44 patients with operable, advanced stage head and neck squamous cell carcinoma treated with two preoperative doses of either glycoengineered imgatuzumab (GA201; 700 or 1400 mg) or cetuximab (standard dosing) in a neoadjuvant setting with paired pre- and post-treatment tumor biopsies. RESULTS: Significant antitumor activity was observed with both antibodies after just two infusions. Metabolic responses were seen in 23 (59.0%) patients overall. One imgatuzumab-treated patient (700 mg) achieved a 'pathological' complete response. An immediate and sustained decrease in peripheral natural killer cells was consistently observed with the first imgatuzumab infusion but not with cetuximab. The functionality of the remaining peripheral natural killer cells was maintained. Similarly, a pronounced increase in circulating cytokines was seen following the first infusion of imgatuzumab but not cetuximab. Overall, tumor-infiltrating CD3+ cell counts increased following treatment with both antibodies. A significant increase from baseline in CD3+/perforin+ cytotoxic T cells occurred only in the 700-mg imgatuzumab group (median 95% increase, P < 0.05). The most prominent decrease of EGFR-expressing cells was recorded after treatment with imgatuzumab (700 mg, -34.6%; 1400 mg, -41.8%). The post-treatment inflammatory tumor microenvironment was strongly related to baseline tumor-infiltrating immune cell density, and baseline levels of EGFR and pERK in tumor cells most strongly predicted therapeutic response. CONCLUSIONS: These pharmacodynamic observations and relationship with efficacy are consistent with the proposed mode of action of imgatuzumab combining efficient EGFR pathway inhibition with ADCC-related immune antitumor effects. CLINICAL TRIAL REGISTRATION NUMBER: NCT01046266 (ClinicalTrials.gov).

[The thin ALT perforator flap for oropharyngeal robotic-assisted reconstruction]. / Le lambeau libre perforant antérolatéral de cuisse fin dans les reconstructions oropharyngées robot-assistées.

Since a few years, the transoral robotic surgery reduced the morbidity of oropharyngeal tumors excision. Large posterior tumors can now be removed without any scar visible on the face. In this context and to respect the thinness required for reconstructions at the junction of the upper aerodigestive tract, the free radial forearm flap still remains the solution of choice. However, if the transoral robotic surgery respects the anatomy and the aesthetics of patients at the visible and social area that represents the face, the forearm flap provides visible scars on the other region of social interaction that represents the upper limb. The aim of our work was to prove the feasibility and the benefits in terms of reducing sequelae when using a thin anterolateral perforator flap harvested above the plane of the superficial fascia. We present this new original method in detail and the advantages it offers to patients after surgery.

[Harvesting technique of chimeric multiple paddles fibular flap for wide oromandibular defects]. / Technique de prélèvement du lambeau de fibula chimérique multipalettes pour la reconstruction des larges defects oromandibulaires.

Carcinological head and neck reconstruction still remains a challenge due to the volume and varied tissues needed. Large and wide oromandibular defects require, not just the bone but also soft tissues for the pelvilingual reconstruction and therefore, a second free flap may become necessary in addition to a fibular flap. The option of an unique chimeric flap based on the fibular artery and its branches is less known whereas it offers the advantage of a unique flap with bone, muscle and multiple skin paddles, independent of each other. The aim of this technical note is to present step by step the surgical procedure of this chimeric flap and share this method that avoids a second free flap.

Squamous cell carcinoma of the larynx with subglottic extension: is larynx preservation possible?

PURPOSE: Squamous cell carcinoma of larynx with subglottic extension (sSCC) is a rare location described to carry a poor prognosis. The aim of this study was to analyze outcomes and feasibility of larynx preservation in sSCC patients. PATIENTS AND METHODS: Between 1996 and 2012, 197 patients with sSCC were treated at our institution and included in the analysis. Stage III-IV tumors accounted for 76%. Patients received surgery (62%), radiotherapy (RT) (18%), or induction chemotherapy (CT) (20%) as front-line therapy. RESULTS: The 5-year actuarial overall survival (OS), locoregional control (LRC), and distant control rate were 59% (95% CI 51-68), 83% (95% CI 77-89), and 88% (95% CI 83-93), respectively, with a median follow-up of 54.4 months. There was no difference in OS and LRC according to front-line treatments or between primary subglottic cancer and glottosupraglottic cancers with subglottic extension. In the multivariate analysis, age > 60 years and positive N stage were the only predictors for OS (HR 2, 95% CI 1.2-3.6; HR1.9, 95% CI 1-3.5, respectively). A lower LRC was observed for T3 patients receiving a larynx preservation protocol as compared with those receiving a front-line surgery (HR 14.1, 95% CI 2.5-136.7; p = 0.02); however, no difference of ultimate LRC was observed according to the first therapy when including T3 patients who underwent salvage laryngectomy (p = 0.6). In patients receiving a larynx preservation protocol, the 5-year larynx-preservation rate was 55% (95% CI 43-68), with 36% in T3 patients. The 5-year larynx preservation rate was 81% (95% CI 65-96) and 35% (95% CI 20-51) for patients who received RT or induction CT as a front-line treatment, respectively. CONCLUSION: Outcomes of sSCC are comparable with other laryngeal cancers when managed with modern therapeutic options. Larynx-preservation protocols could be a suitable option in T1-T2 (RT or chemo-RT) and selected T3 sSCC patients (induction CT).

Occult nodal metastases in T1-T2cN0 oral squamous cell carcinoma: Correlation between sentinel node positivity and completion neck dissection analysis.

OBJECTIVES: Sentinel node procedure (SN) is a standard procedure that has shown its safety and effectiveness for T1/T2 cN0 oral squamous cell carcinoma (OSCC), with completion neck dissection (CND) for patients with positive SN. The aim of this study was to characterize the nodal involvement in a cohort of SN + OSCC. MATERIALS AND METHODS: Patients with T1/T2 cN0 OSCC with positive SN with CND were included in this single-center, prospective cohort study between 2000 and 2013. RESULTS: 54/301 patients had at least one positive SN. In 43/54 (80 %) cases, only the SN(s) were invaded; with only one SN involved (SN+=1) in 36/54 (67 %) cases. No predictive factors of nodal involvement in the CND were found considering the followings: SN micro/macrometastases, primary tumor's depth of invasion (DOI), perineural spread, lymphovascular involvement, primary tumor location, T stage and extranodal extension. The SN micrometastatic involvement (n = 22) was significantly associated with only one SN + CND- (p = 0.017). In the group of patients with unique micrometastatic involvement in the SN (n = 20/54), there was a higher isolated nodal recurrence free time (p = 0.017). CONCLUSION: 80% of T1/T2 cN0 OSCC with positive SN had no other lymph node metastases in the CND, questioning the potential benefits of this procedure. Predictive factors such as the size of the SN metastasis need to be tested to stratify the risk of positive non-SN lymph nodes leading to a personalized treatment, lowering the therapeutic morbidity while maintaining the oncologic safety.

Postgraduate oncology educational shifts during the COVID-19 pandemic: results of faculty and medical student surveys.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has disrupted clinical practice, research and teaching. During peaks, virtual courses were implemented but these changes are poorly described, especially for oncology postgraduate students and faculty teachers. PATIENTS AND METHODS: We administered two surveys from June 2021 to October 2021 to students and faculty teachers (250 and 80 responses, respectively) who registered at Gustave Roussy School of Cancer Sciences (Université Paris-Saclay) during 3 consecutive university years (October 2018 to October 2021), where a major shift to e-learning was associated with COVID-19 pandemic. RESULTS: Most students were female (53%), attending physicians (50%), aged 30-39 years (54%) and 2020-2021 (66.4%) was the main year of training. Most faculty teachers were male (58%), aged 40-50 years (44%) and had participated in training for at least 3 years (83%). More than half of the students received 100% virtual training [55% versus 45% face-to-face/mixed teaching modalities; online (84%) versus remote teaching (16%)]. Only 34% of students declared >80% 'active listening' and only 16% of teachers considered e-learning to be more suitable (compared with face-to-face) for postgraduate education. Virtual teaching decreased student-teacher interactions as compared with mixed/face-to-face (lessons were sufficiently interactive for 54% students if virtual only teaching versus for 71% if other teaching modalities; P = 0.009). Teachers stated that virtual learning did not lead to any improvements in terms of attendance (68%), interaction (74%) and quality of teaching (68%). However, most faculty (76%) acknowledged that partial e-learning training should be maintained outside the pandemic, if it represents ≤50% of the whole teaching (teachers: 79% versus student: 66%; P = 0.04). CONCLUSIONS: COVID-19 accelerated the transition toward novel practices. Students and faculty teachers agreed on the need for future mixed (≤50% e-learning) teaching modalities. Adequate formation and the use of codified best newer virtual practices are required.

Effects of lapatinib monotherapy: results of a randomised phase II study in therapy-naive patients with locally advanced squamous cell carcinoma of the head and neck.

BACKGROUND: Lapatinib is a dual inhibitor of epidermal growth factor receptor (EGFR) and human EGFR-2 (HER-2) tyrosine kinases. This study investigated the pharmacodynamic and clinical effects of lapatinib in patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN). METHODS: In total, 107 therapy-naive patients with locally advanced SCCHN were randomised (2 : 1) to receive lapatinib or placebo for 2-6 weeks before chemoradiation therapy (CRT). Endpoints included apoptosis and proliferation rates, clinical response, and toxicity. RESULTS: Versus placebo, lapatinib monotherapy did not significantly increase apoptosis detected by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick-end labelling or caspase-3 assays. A statistically significant decrease in proliferation using Ki67 assay was observed (P=0.030). In a subset of 40 patients that received 4 weeks of lapatinib or placebo, objective response rate (ORR) was 17% (n=4/24) vs 0% (n=0/16). In the lapatinib single-agent responders, all had EGFR overexpression, 50% had EGFR amplification, and 50% had HER2 expression by immunohistochemistry (including one patient with HER2 amplification). However, these patients showed variable modulation of apoptosis, proliferation, and phosphorylated EGFR on drug treatment. Following CRT, there was a statistically non-significant difference in ORR between lapatinib (70%) and placebo (53%). There was no clear correlation between changes in apoptosis or proliferation and response to chemoradiation. Mucosal inflammation, asthenia, odynophagia, and dysphagia were the most commonly reported adverse events with lapatinib. CONCLUSION: Short-term lapatinib monotherapy did not demonstrate apoptotic changes, but provided evidence of clinical activity in locally advanced SCCHN, and warrants further investigation in this disease.

Replacement of lip-split mandibulotomy by pull-through approach for T3-4 oral carcinomas.

At the study hospital, the lip-split mandibulotomy (LSM) has progressively been replaced by a pull-through (PT) approach. This study compared the outcomes of the LSM and PT approaches in a series of 192 patients with T3-T4a oral tongue and floor of the mouth squamous cell carcinoma treated over the two last decades. No difference in margin status (P = 0.254), rate of early complications (local infections) (P = 0.867), haematoma/haemorrhage (P = 0.221), delayed wound healing (P = 0.438), re-operation (P = 0.083), or Clavien-Dindo classification (P= 0.5281) was found. The LSM approach was associated with a higher rate of late complications such as pseudarthrosis (14.5% vs 0.9%; OR 17.89, P = 0.0005) and trismus (35% vs 13.8%; OR 3.32, P = 0.025), and a trend towards a higher rate of fistulas (24.6% vs 13.1%; OR 2.16, P = 0.088). The quality of life of long-term survivors (median 132 months) was similar in the two groups, with a mean QLQC30 score of 59.7 (P = 0.099) and mean MDADI score of 57.4 (P = 0.213). The 5-year local control rate was 86.4% in the PT group and 86.2% in the LSM group (P = 0.878), while the 5-year overall survival rates were 50.0% and 48.3%, respectively (P = 0.68). In our experience, replacement of LSM by a PT approach in oral carcinoma was associated with decreased rates of late complications such as pseudarthrosis, fistula, and trismus, without any difference in oncological outcomes.

French consensus on management of head and neck cancer surgery during COVID-19 pandemic.

In the context of the current pandemic, there is a need for specific advice concerning treatment of patients with Head and Neck cancers. The rule is to limit as much as possible the number of patients in order to reduce the risks of contamination by the SARS-Cov-2 virus for both patients and the caregivers, who are particularly exposed in ENT. The aim is to minimize the risk of loss of opportunity for patients and to anticipate the increased number of cancer patients to be treated at the end of the pandemic, taking into account the degree of urgency, the difficulty of the surgery, the risk of contaminating the caregivers (tracheotomy) and the local situation (whether or not the hospital and intensive care departments are overstretched).

Reconstruction of maxillectomy and midfacial defects using latissimus dorsi-scapular free flaps in a comprehensive cancer center.

BACKGROUND: The standard of care for sinonasal malignancies is a large surgical resection followed by radiotherapy. Midfacial defects resulting from maxillectomy require a complex reconstruction procedure. Given their adaptability, chimeric flaps such as latissimus dorsi-scapular (LDS) free flaps appear to be a good option. MATERIAL & METHODS: We performed a single-center retrospective study of consecutive patients with sinonasal cancers where a LDS free flap was used for reconstruction. We assessed the postoperative complications and the functional, aesthetic and oncologic outcomes. RESULTS: Eighty-four patients were included. Primary tumors were staged as T4a in 68% of cases; 38.3% of the patients received induction chemotherapy and 82.7% received adjuvant radiotherapy. Based on our classification of midfacial and palatal defects, the majority of the patients (69%) had a type IIa with interruption of the three facial pillars. The orbital floor was removed in 55.9% of cases. The median follow-up was 45 months. Total flap necrosis with no possible revascularization occurred in 5.9% of cases. For the orbital reconstruction, a revision procedure was needed for necrosis and/or infection of the costal cartilage graft in eight cases (17%). More than 90% of the patients had no functional disorders regarding speaking, swallowing and chewing. Soft palate involvement was a prognostic factor of speech (p < 10-4) and swallowing (p = .005) disorders. Dental rehabilitation was realized in 70.2% of the patients. No severe complications were observed in the donor site, except for one seroma. CONCLUSION: A LDS free flap is a reliable technique for the reconstruction of complex midfacial defects.

Quantitative methylation analyses of resection margins predict local recurrences and disease-specific deaths in patients with head and neck squamous cell carcinomas.

This study sought to determine whether the presence of hypermethylated genes in the surgical margins can predict local recurrences in head and neck squamous cell carcinomas (HNSCCs). We prospectively collected tumour and surgical margin specimens from patients with HNSCCs who had undergone surgical resections. Quantitative methylation-specific PCR (QMSP) of CDKN2A, CCNA1 and DCC were performed in these specimens and correlated with clinical data. Of the 42 patients eligible for the study, 27 were hypermethylation informative for the above three genes. This latter group was associated with longer disease-free survivals (P=0.007) and longer time to disease-specific deaths (P=0.004). Multivariate analyses confirmed hypermethylation non-informative tumours as an independent prognosticating factor for disease-specific deaths (risk ratio 3.8, P=0.026). Quantitative MSP of the margins of 24 hypermethylation informative tumours revealed that 11 patients had molecularly positive margins, of which, five developed disease-specific events (DSEs, three local recurrences and two metastases), compared to none in patients with molecularly negative margins, after a median follow-up of 48 months. Log-rank analyses showed that molecularly positive margins were associated with shorter time to local recurrences and disease-specific deaths (P=0.03 and 0.01, respectively). This study demonstrated that QMSP of hypermethylated promoters in surgical margins predicted all the local recurrences in our series of HNSCC patients. We have also identified hypermethylation non-informative tumours as an independent predictor for the development of DSEs.

[The musculo-mucosal facial artery flap: harvesting technique and indications]. / Le lambeau musculomuqueux de buccinateur pédiculé sur l'artère faciale : technique de prélèvement et indications.

OBJECTIVES: Describe the anatomy and the harvesting technique of the facial artery musculo-mucosal flap (FAMM) and precise its indications in head and neck reconstruction. METHODS: Retrospective review of our experience and review of the literature. RESULTS: Described by Pribaz et al. [Plast Reconstr Surg 90 (1992) 421-9] in 1992, the FAMM flap relies on the facial artery and can be used with a superior or inferior base depending on the deficit to be reconstructed. Venous drainage is usually assured by buccal plexus veinules instead of the facial vein. In our experience, the FAMM flap has been used mainly for limited soft tissue defects of the oral cavity following cancer ablation. Other indications were coverage of oropharyngeal, intranasal and orbital defects. The FAMM flap has also been used to treat mandibular osteoradionecrosis. CONCLUSIONS: Harvesting of the FAMM flap is easy and safe. This flap shows versatility in head and neck reconstruction.

Ethmoid tumor and oncogenic osteomalacia: Case report and review of the literature.

INTRODUCTION: Oncogenic osteomalacia is a very rare disease usually caused by a phosphaturic mesenchymal tumor, particularly the "mixed connective tissue type", secreting FGF-23 hormone. OBJECTIVE: The authors report a case of ethmoid tumor associated with oncogenic osteomalacia and discuss management based on a review of the literature. CASE SUMMARY: A 41-year-old woman with multiple fractures causing major disability was diagnosed with early-onset osteoporosis. CT scan followed by MRI, performed due to the concomitant presence of nasal obstruction, showed a right ethmoid tumor in contact with the dura mater and periorbital tissues, but with no signs of invasion. Endoscopic resection was performed with reconstruction of the defect of the cribriform plate by a nasoseptal flap. Nasal and bone symptoms subsequently resolved. Histological examination revealed a phosphaturic mesenchymal tumor. DISCUSSION: Twelve cases of mesenchymal tumor of the ethmoid sinus associated with oncogenic osteomalacia have been reported to date. FGF-23 assay and whole-body MRI with STIR sequence are useful for the diagnosis. A very favorable outcome is observed after surgical treatment in the majority of cases.

Cervical-transoral robotic oropharyngectomy and thin anterolateral thigh free flap.

The transoral robotic oropharyngectomy surgical technique was initially described for resection of small stage T1 or T2 lesions and the surgical defect is usually allowed to heal by secondary intention. We propose a refined surgical approach adapted to more complex situations such as salvage surgery and surgery in an irradiated field, based on previous experience in open approaches for oropharyngeal cancer. Via a combined cervical-transoral approach, we perform en bloc resection of the parapharyngeal space combined with transoral robotic lateral oropharyngectomy. Reconstruction of the surgical defect is performed with a thin anterolateral thigh free flap.

Sentinel node biopsy in early oral squamous cell carcinomas: Long-term follow-up and nodal failure analysis.

OBJECTIVES: Evaluate the reliability of sentinel node biopsy (SNB) in T1/T2 cN0 oral squamous cell carcinoma (OSCC), and compare recurrence-free time (RFT) and overall survival (OS) between patients undergoing SNB and neck dissection (ND). PATIENTS AND METHODS: Patients with T1/T2 cN0 OSCC underwent SNB followed by systematic ND in the first cohort and SNB followed by selective ND in case of positive sentinel nodes (SN) in the second cohort. RESULTS: A total of 229 patients were followed (first cohort 50, second cohort 179). SNs were successfully detected in 93.9% (215/229) of cases. Median follow-up was 5.6 years. Recurrence occurred in 38/215 patients, with isolated nodal recurrence in 18/215 patients. At 5 years, the rate of recurrence-free patients was 80.0% and the rate of patients without isolated nodal recurrence was 90.4%. Negative predictive value of SNB was 92.7%. No statistically significant difference was observed between the two groups regarding RFT and OS. In 83% (10/12) of ipsilateral isolated nodal recurrences, primary tumor was located in anterior part of oral cavity. Only 43% (3/7) of SN+ patients with nodal recurrence were eligible for salvage surgery, compared to 91% (10/11) of SN- patients. SNB resulted in fewer complications than ND (8% vs 28%, p < 0.0001). CONCLUSION: SNB is a reliable staging tool for T1/T2 cN0 OSCC, without adverse effect on patient survival and fewer complications. No late recurrences occurred in long-term follow-up. Close follow-up is mandatory for SN+ patients, who are at higher risk of nodal recurrence and have worse prognosis.

[New developments in the management of nasopharyngeal carcinoma]. / Nouveautés dans la prise en charge des carcinomes nasopharyngés.

Nasopharyngeal carcinoma is a rare condition, with less than 300 cases occurring per year in France. Its treatment can be difficult due to the importance of side effects, but tumor control is usually excellent following a well conducted chemoradiotherapy. This article summarizes the recent advances in nasopharyngeal cancer diagnosis, classification, treatment, surveillance and management of recurrences. Chemotherapy timing is discussed, along with arguments in favor of induction chemotherapy in locally advanced cases. As a survival advantage has been suggested for when patients are treated in high volume center it seems reasonable to refer these young patients for treatment to tertiary expert centers, especially given the low incidence of the disease.