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.

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.

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.

[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.

Larynx preservation in pyriform sinus cancer: preliminary results of a European Organization for Research and Treatment of Cancer phase III trial. EORTC Head and Neck Cancer Cooperative Group.

BACKGROUND: As a general rule, surgery whenever possible, followed by irradiation is considered to be the standard treatment for cancer of the hypopharynx, thus sacrificing natural speech. In most patients, surgery includes removal of the larynx. PURPOSE: A prospective, randomized phase III study was conducted by the European Organization for Research and Treatment of Cancer (EORTC) starting in 1990 to compare a larynx-preserving treatment (induction chemotherapy plus definitive, radiation therapy in patients who showed a complete response or surgery in those who did not respond) with conventional treatment (total laryngectomy with partial pharyngectomy, radical neck dissection, and postoperative irradiation) in previously untreated and operable patients with histologically proven squamous cell carcinomas of the pyriform sinus or aryepiglottic fold, but free of other cancers. METHODS: Patients were randomly assigned to one of two treatment arms: 1) immediate surgery with postoperative radiotherapy (50-70 Gy) or 2) induction chemotherapy (cisplatin [100 mg/m2] given as a bolus intravenous injection on day 1, followed by infusion of fluorouracil [1000 mg/m2 per day] on days 1-5). An endoscopic evaluation was performed after each cycle of chemotherapy. After two cycles, only partial and complete responders received a third cycle. Patients with a complete response after two or three cycles of chemotherapy were treated thereafter by irradiation (70 Gy); nonresponding patients underwent conventional surgery with postoperative radiation (50-70 Gy). Salvage surgery was also performed when patients relapsed after chemotherapy and irradiation. The trial was designed to test the equivalence of the two treatment arms; i.e., the induction chemotherapy treatment would be judged equivalent to immediate surgery if the relative risk of death for induction chemotherapy compared with immediate surgery was significantly less than 1.43 using a one-sided hypothesis test at the .05 level of significance. RESULTS: Two hundred two patients entered the trial and were randomly assigned; only 194 were eligible for treatment (94 in the immediate-surgery arm and 100 in the induction-chemotherapy arm). In the induction-chemotherapy arm, complete response was seen in 52 (54%) of 97 patients with local disease (primary tumor) and in 31 (51%) of 61 patients with regional disease (involvement of the neck). Treatment failures at local, regional, and second primary sites occurred at approximately the same frequencies in the immediate-surgery arm (12%, 19%, and 16%, respectively) and in the induction-chemotherapy arm (17%, 23%, and 13%, respectively). In contrast, there were fewer failures at distant sites in the induction-chemotherapy arm than in the immediate-surgery arm (25% versus 36%, respectively; P = .041). The median duration of survival was 25 months in the immediate-surgery arm and 44 months in the induction-chemotherapy arm and, since the observed hazard ratio was 0.86 (logrank test, P = .006), which was significantly less than 1.43, the two treatments were judged to be equivalent. The 3- and 5-year estimates of retaining a functional larynx in patients treated in the induction-chemotherapy arm were 42% (95% confidence interval = 31%-53%) and 35% (95% confidence interval = 22%-48%), respectively. CONCLUSIONS AND IMPLICATIONS: Larynx preservation without jeopardizing survival appears feasible in patients with cancer of the hypopharynx. On the basis of these observations, the EORTC has now accepted the use of induction chemotherapy followed by radiation as the new standard treatment in its future phase III larynx preservation trials.

Experimental studies and preliminary clinical trial of vinorelbine-loaded polymeric bioresorbable implants for the local treatment of solid tumors.

Vinorelbine is a new 5' nor Vinca alkaloid, active by i.v. route, in various types of cancer disease such as non-small cell lung cancer and advanced breast cancer. In order to evaluate the possibility of using this drug for local treatment of cancer, Vinorelbine-loaded bioresorbable polymeric implants were prepared using a copolymer of D,L-lactic and glycolic acids (PLA 37.5 GA 25). According to the manufacturing process, the 1.2-mm-diameter cylindrical rods obtained had a drug content of 1, 5, or 20% (w/w) and released half of their content within about 6 days in vitro. In vivo release in rats was slower, half of the drug being released after about 14 days. A dose-dependent antitumoral effect was observed in mice (solid P388 leukemia model) when implants were administered into or in contact with the tumor. At highest drug loads and when administered soon after tumor implantation, Vinorelbine implants were more effective than i.v. administration (median survival time of treated animals related to untreated controls, greater than 360 versus 188). In dogs, results of toxicity experiments revealed that administration of implants in vital organs must be avoided. On the contrary, s.c. administration was well tolerated. A transient local necrosis was observed in the days following implantation, but normal skin was recovered after about 10 weeks. Thus, a clinical trial was conducted on patients with head and neck cancer; implantation of 20% loaded polymeric implants into the tumor sites succeeded in 8 of 9 patients. The sole failure was attributed to the unusual hardness of the tumor tissue. Except for a local transient inflammatory reaction (easily treated with nonsteroidal antiinflammatory agents), no other sign of toxicity was detected, and patients tolerated the device well. Fourteen days after implantation, patients underwent their planned surgery, and the implants were recovered. Residual drug content varied from 24 to 55%. In all cases, there was a clearly delimited necrotic area around the implant, ranging from 0.5 to 3.5 cm in diameter. In the smallest tumors, necrosis was also observed in the normal tissue inside this area. These results invite further studies to evaluate such drug-loaded polymeric implants.

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.

Modification of the infra hyoid musculo-cutaneous flap.

BACKGROUND: In 1986, Wang described the infra hyoid musculo-cutaneous flap. Here, we report technical adaptations and improvements to this flap. METHODS: From 1994 to 1996, we performed 61 infrahyoid flaps using the classical procedure. After 5 years of technical evolution, we studied a new series of 91 flaps from January 2000 to June 2002. We reviewed our experience with the infra hyoid flap and described the surgical procedure, its evolution and the impact on the viability of the flap. RESULTS: In the two series, the main arterial pedicle was usually the superior thyroid artery. Venous drainage was more variable; consequently we always performed a modified neck dissection with preservation of the internal jugular vein. In the first series, the surgical results were good with only seven local complications essentially skin necrosis. The functional and aesthetic results seemed acceptable. In the second series, the results, after technical evolution with better venous drainage and cervical closure, were improved (only one necrosis) and the indications were extended. CONCLUSION: With experience, the infra hyoid myocutaneous flaps is reliable and appears as a particularly useful flap for oral cavity, oral pharynx and pharyngeolaryngeal reconstruction.

[Larynx preservation, state of the art]. / La préservation laryngée, état de la question.

Larynx preservation in advanced pharyngolaryngeal cancers has been a major challenge in clinical research over the past two decades. Subtotal surgery (endoscopic laser surgery, supracricoid partial laryngectomies and hemilaryngopharyngectomies) has allowed reducing the indications of the so-called "mutilating" surgery. On the other hand, the modification of fractionation has notably improved the results of definitive irradiation (but most probably for supraglottic tumors). The main clinical research has been carried out with either sequential or concurrent chemo-irradiation. Induction chemotherapy followed by irradiation in good responders or by surgery in poor responders allowed to preserve the larynx in around half the cases without deleterious impact on overall survival. Concurrent chemo-irradiation trials suggested that the larynx preservation rates could be increased but overall survival remained unchanged and mucositis was a notable side effect. The next step could be the combination of induction chemotherapy followed by concurrent chemo-irradiation in good responders. Finally, the place of new drugs (taxanes, targeted therapies) is to be explored in this context.

Randomised EORTC head and neck cooperative group trial of preoperative intra-arterial chemotherapy in oral cavity and oropharynx carcinoma.

Between February 1978 and January 1984, 222 eligible patients were randomised in a multicentre trial of preoperative intra-arterial chemotherapy in the treatment of oral cavity and oropharynx carcinoma. Patients were randomised between either surgery or preoperative chemotherapy. This latter group received vincristine and bleomycin for 12 days. Patients were stratified according to the primary site: floor of the mouth (FM) versus posterior oral cavity or oropharynx (POC) and institution. The FM group received postoperative radiotherapy depending upon quality of the margins and lymph-node pathological involvement, when it was systematically applied in the POC group. Tumour regression after chemotherapy either complete (CR) or partial (PR greater than 50%) was observed in 48% in the FM group and 41% in the POC group, and lymph-node regression (CR + PR) was respectively 15% and 23%. Some discrepancies appeared between clinical regression and pathological response, and the number of cases without histological response was clearly higher than the number of cases without clinical response. The overall survival showed a statistically significant difference (P = 0.048) between FM and POC groups. In the FM group, median survival in the chemotherapy arm was estimated at 7 years compared with 3 years in the surgery arm. In the POC group, median survival was estimated at 3 years in both treatment arms. Chemotherapy lowered the uncontrolled disease and local recurrence in the FM group. These differences do not exist in the POC group, which may be due to the systematically postoperative radiotherapy.

French version of FACT-G: validation and comparison with other cancer-specific instruments.

The aim of this study was to assess the validity of the French version of the Functional Assessment of Cancer Therapy - General (FACT-G), and to compare its psychometric properties with those of two other cancer-specific quality of life questionnaires, European Organisation for Research and Treatment of Cancer Quality of Life - Core 30 (EORTC QLQ-C30) and Functional Living Index - Cancer (FLIC). Two hundred and twenty three patients with breast or colorectal cancer completed the FACT-G questionnaire in French followed by (in random order) the QLQ-C30 and FLIC. An additional 87 patients with head and neck (H&N) cancer completed the FACT-H&N followed by the QLQ-C30 and H&N-Besançon. The French version of FACT-G was internally consistent, and its reproducibility was excellent. FACT-G Physical Well-Being and global scores correlated with all QLQ-C30 subscales. There was evidence of discriminant validity. Compared with the other tools, FACT-G included a statistically significantly higher proportion of items patients considered to be confusing or upsetting. Patients with breast or colorectal cancer expressed a preference for QLQ-C30. Use of the specific H&N additional items increased the responsiveness to change of FACT-G. The French version of FACT-G is valid and has psychometric properties similar to those of FLIC and QLQ-C30.

From chemoprevention and organ preservation programmes to postoperative management: major achievements and strategies of the EORTC Head and Neck Cancer Group.

The purpose of this article is to review the most significant results of the clinical studies conducted in the past two decades by the EORTC Head and Neck Cancer Group (HNCG). As for phase III trials, the HNCG investigated, besides the efficacy of chemopreventive drugs, the impact of cytostatic agents on various therapeutic targets, in combination or not with surgery and chemotherapy. These targets were: (a) chemo-prevention in curatively treated early stage disease; (b) organ preservation programmes in patients with operable tumour, comparing immediate surgery versus first-line chemotherapy; (c) postoperative management of locally advanced tumours, comparing radio-chemotherapy versus radiotherapy alone. Other phase II and phase III studies were also completed to investigate drug activity in advanced and/or recurrent head and neck squamous cell and adenoid cystic carcinomas. The present article will also analyse the strategies developed within the Group in the field of translational research.

Epithelioid sarcoma of the tongue.

A case of epithelioid sarcoma in the tongue is reported. The patient, a 35 year old woman, presented with a non-ulcerated painful lesion of the tongue. Microscopically, the tumour was characterised by multiple coalescent nodules with central geographic necrosis infiltrating the lingual muscle. The tumour cells were epithelioid with abundant eosinophilic cytoplasm and atypical nuclei. Immunohistochemically, the tumour cells stained for vimentin, keratin, and epithelial membrane antigen. These morphological and immunohistochemical appearances led to the diagnosis of epithelioid sarcoma of the tongue. Seven years later, the patient died with metastatic dissemination to the scalp, lungs, and brain. No case of epithelioid sarcoma arising in the tongue has been described previously.

A phase II study of pirarubicin in patients with advanced recurrent head and neck squamous cell carcinoma.

BACKGROUND: Head and neck squamous carcinoma (HNSCC) is a chemotherapy-sensitive tumour, but this sensitivity is not reflected in an impact on survival. The study of new drugs is therefore indicated. Pirarubicin (4'-O-tetrahydropyranyl-doxorubicin) has a higher preclinical index than doxorubicin, with low cardiotoxicity in animal models. PATIENTS AND METHODS: Twenty-six patients with squamous cell carcinoma of the head and neck and documented progression after or during previous chemotherapy were entered into the study. Two patients were ineligible for evaluation. Pirarubicin was given at a dose of 70 mg/m2 every 3 weeks. RESULTS: Partial remission was seen in 1 of the 24 evaluable patients. The predominant toxicity was bone marrow depression, with leucopenia in 62% of the patients. One patient died due to a gastrointestinal haemorrhage during a period with WHO grade IV thrombocytopenia. CONCLUSION: On the basis of these results, pirarubicin cannot be recommended as second-line treatment in patients with recurrent and metastatic HNSCC. Its possible relevance for first-line treatment cannot be judged from these data.

Platinum concentration in human tumors of head and neck, uterine cervix, and breast following treatment with cisplatin.

Intratumoral platinum concentrations were measured in three tumor sites (head and neck, uterine cervix, and breast) 48 h after cisplatin administration according to the same protocol. The platinum levels were in the same order of magnitude in all tumors, but the concentration in breast tumors was found to be higher than that in tumors of the head and neck and of the uterine cervix.