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To assess the use of radiotherapy (RT) or concurrent chemoradiotherapy (CRT) following taxane-based induction chemotherapy (T-ICT) in locally advanced head and neck squamous cell carcinoma (LAHNSCC) and to evaluate the tolerability of CRT after T-ICT. From 01/2006 to 08/2012, 173 LAHNSCC patients treated as a curative intent by T-ICT, followed by definitive RT/CRT were included in this analysis. There was an 86% objective response (OR) after ICT among 154 evaluable patients. Forty-four patients received less than three cycles (25%) and 20 received only one cycle of T-ICT. The 3-year actuarial overall survival (OS) was 49% and there was no OS difference according to the type of ICT (regimen or number of cycle) or the addition of concurrent CT (cisplatin, carboplatin, or cetuximab) to RT. In multivariate analysis (MVA), clinically involved lymph node (cN+), age more than 60 years, the absence of OR after ICT, and performance status of at least 1 predicted for a decreased OS, with hazard ratios (HR) of 2.8, 2.2, 2.1, and 2, respectively. The 3-year actuarial locoregional control (LRC) and distant control (DC) rates were 52 and 73%, respectively. In MVA, the absence of OR after ICT (HR: 3.2), cN+ (HR: 3), and age more than 60 years (HR: 1.7) were prognostic for a lower LRC whereas cN+ (HR: 4.2) and carboplatin-based T-ICT (HR: 2.9) were prognostic for a lower DC. The number of cycles (≤ 2) received during ICT was borderline significant for DC in the MVA (P=0.08). Among patients receiving less than or equal to three cycles of ICT, higher outcomes were observed in patients who received cisplatin-based T-ICT (vs. carboplatin-based T-ICT) or subsequent CRT (vs. RT). T-ICT in our experience, followed by RT or CRT, raises several questions on the role and type of induction, and the efficacy of CRT over RT. The role of RT or CRT following induction, although feasible in these advanced patients, awaits answers from randomized trials.

Purpose: This study sought to determine the maximum tolerated dose (MTD) of oral etoposide in combination with radiotherapy in head and neck squamous cell carcinoma (HNSCC)., Patients and Methods: Phase I, multicenter, open-labelled, non-comparative and dose escalating trial. Patients with locally advanced HNSCC were enrolled onto cohorts of escalating dose of etoposide. Oral etoposide was administered on five consecutive days every week for 7 weeks (7 treatment cycles) in combination with daily radiotherapy (70 Gy /35 fractions). Two dose levels (25 mg/day and 50 mg/day) of etoposide were planned and three to six patients were to be enrolled at each level according to the potential DLTs., Results: Fourteen patients were allocated to two dose levels: 25 mg/day (3) and 50 mg/day (11). Cisplatin was contra-indicated in all the patients included. Only one patient (50 mg/day) presents a grade 4 neutropenia (DLT), no other DLTs were observed. The most frequently adverse events (AEs) were radiomucositis. Two deaths before 3 months of end of treatment were not related to treatment. Seven patients were still alive with a median follow-up of 30 months (12-58 months). Nine patients had a complete response (CR) at 3 months after the radiotherapy; Among the 9 patients, 3 patients had a local relapse; one patient with local and distant relapse., Conclusion: Due to only one DLT experienced, it is possible to a dose of 50 mg/day for phase II studies, however this should be considered with caution.

Background: Concomitant chemoradiotherapy and accelerated radiotherapy independently improve outcomes for patients with locally advanced head and neck squamous-cell carcinoma (HNSCC). We aimed to assess the efficacy and safety of a combination of these approaches., Methods: In our open-label phase 3 randomised trial, we enrolled patients with locally advanced, stage III and IV (non-metastatic) HNSCC and an Eastern Cooperative Oncology Group performance status of 0-2. We randomly allocated patients centrally with a computer program (with centre, T stage, N stage, and localisation as minimisation factors) in a 1:1:1 ratio to receive conventional chemoradiotherapy (70 Gy in 7 weeks plus three cycles of 4 days' concomitant carboplatin-fluorouracil), accelerated radiotherapy-chemotherapy (70 Gy in 6 weeks plus two cycles of 5 days' concomitant carboplatin-fluorouracil), or very accelerated radiotherapy alone (64·8 Gy [1·8 Gy twice daily] in 3·5 weeks). The primary endpoint, progression-free survival (PFS), was assessed in all enrolled patients. This trial is completed. The trial is registered with ClinicalTrials.gov, number NCT00828386., Findings: Between Feb 29, 2000, and May 9, 2007, we randomly allocated 279 patients to receive conventional chemoradiotherapy, 280 to accelerated radiotherapy-chemotherapy, and 281 to very accelerated radiotherapy. Median follow-up was 5·2 years (IQR 4·9-6·2); rates of chemotherapy and radiotherapy compliance were good in all groups. Accelerated radiotherapy-chemotherapy offered no PFS benefit compared with conventional chemoradiotherapy (HR 1·02, 95% CI 0·84-1·23; p=0·88) or very accelerated radiotherapy (0·83, 0·69-1·01; p=0·060); conventional chemoradiotherapy improved PFS compared with very accelerated radiotherapy (0·82, 0·67-0·99; p=0·041). 3-year PFS was 37·6% (95% CI 32·1-43·4) after conventional chemoradiotherapy, 34·1% (28·7-39·8) after accelerated radiotherapy-chemotherapy, and 32·2% (27·0-37·9) after very accelerated radiotherapy. More patients in the very accelerated radiotherapy group had RTOG grade 3-4 acute mucosal toxicity (226 [84%] of 268 patients) compared with accelerated radiotherapy-chemotherapy (205 [76%] of 271 patients) or conventional chemoradiotherapy (180 [69%] of 262; p=0·0001). 158 (60%) of 265 patients in the conventional chemoradiotherapy group, 176 (64%) of 276 patients in the accelerated radiotherapy-chemotherapy group, and 190 (70%) of 272 patients in the very accelerated radiotherapy group were intubated with feeding tubes during treatment (p=0·045)., Interpretation: Chemotherapy has a substantial treatment effect given concomitantly with radiotherapy and acceleration of radiotherapy cannot compensate for the absence of chemotherapy. We noted the most favourable outcomes for conventional chemoradiotherapy, suggesting that acceleration of radiotherapy is probably not beneficial in concomitant chemoradiotherapy schedules., Funding: French Ministry of Health., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Intensity-modulated radiation therapy (IMRT) is an evolution of 3D conformal radiation therapy, which is the current standard radiation therapy technique in head-and-neck cancer. Modulating the radiation intensity of each beam by dynamic interposition of the computer-assisted collimator leaves yields dose distributions that are particularly well adapted to head-and-neck tumor volumes. It is thus possible to predetermine dose per element: i.e., the minimum effective dose to be delivered to tumor areas, and the maximum to be safely delivered to organs at risk. The technique thereby enables complex tumoral targets to be optimally covered, while sparing healthy tissue, and salivary glands in particular. In addition, the technique allows dose-escalation, with a higher dose per session delivered to the macroscopic tumor than to other irradiated areas. The first results of ongoing randomized trials confirmed those of earlier comparative studies, showing marked improvement in side effects, including post-radiation xerostomia. Although the positive impact of this technique on tumor control remains to be proven, salivary function conservation currently makes IMRT the standard treatment in most head-and-neck cancer., (Copyright © 2011 Elsevier Masson SAS. All rights reserved.)

Purpose: This randomized phase III trial investigated the potential benefit of concurrent re-irradiation, fluorouracil and hydroxyurea versus methotrexate for patients treated with palliative intent for recurrent or second primary head and neck squamous cell carcinoma (HNSCC) in previously irradiated area., Patients and Methods: Patients with recurrent HNSCC or a second primary not amenable to curative-intent treatment were randomized to the R-RT arm (concurrent re-irradiation, fluorouracil and hydroxyurea) or to the Ch-T arm (methotrexate). The primary endpoint was overall survival (OS). Due to a very slow accrual, the trial was closed after inclusion of 57 patients., Results: Fifty-seven patients were included. All patients died in the two arms with a maximal follow-up of 5years. Although four complete responses were achieved in R-RT arm, (none in Ch-T arm) re-irradiation did not improve OS compared with methotrexate (23% versus 22% at 1year, NS). Sixteen patients experienced clinical grade ⩾3 late toxicities (>6months), 11 in R-RT arm and five in Ch-T arm., Conclusions: Premature discontinuation of the trial did not allow us to draw firm conclusions. However, there was no suggestion that concurrent re-irradiation, fluorouracil and hydroxyurea improved OS compared to methotrexate alone in patients treated with palliative intent for a recurrent or second primary HNSCC., (Copyright © 2011. Published by Elsevier Ireland Ltd.)

Purpose of Review: Radiation therapy plays a key role in the management of head and neck cancers (HNCs). We reviewed the recent advances in radiotherapy of HNCs and the role of imaging in treatment planning., Recent Findings: As shown in a recent update of meta-analysis of chemotherapy in head and neck cancer (MACH-NC), concurrent chemoradiotherapy was confirmed to be a standard of care in the management of locally advanced HNCs. Two recent large-scale randomized trials [Groupe d'Oncologie Radiothérapie Tête et Cou (GORTEC) and Radiation Therapy Oncology Group (RTOG)] failed to show additional benefit when combining accelerated radiotherapy with concurrent chemoradiotherapy. Updated 5-year results of a phase III pivotal trial confirmed the benefit of targeting epidermal growth factor receptor with cetuximab when combined with radiotherapy. Taxane-platinum-fluorouracil-based induction chemotherapy has been established as a reference induction regimen and has been explored as a possible part of the treatment of locally advanced HNCs, which was particularly successful in larynx preservation. The superiority of intensity-modulated radiation therapy compared with conventional radiotherapy for parotid protection has been shown in a prospective phase III trial. PET-based treatment planning is still to be validated in the HNCs., Summary: Concurrent chemoradiotherapy could still be considered as a standard of care; several new treatment combinations and new radiation technologies have been recently successfully evaluated in clinical trials.

Duration of the G2-phase delay and arrest after exposure to ionizing radiation is thought to influence radiosensitivity. The kinase activity of the p34cdc2-cyclin B complex and the p34cdc2-cyclin A complex is implicated in G2- to M-phase transition and in G2-phase arrest after exposure to ionizing radiation. We analyzed the expression level and the subcellular location of p34cdc2, cyclin A and cyclin B in head and neck squamous cell carcinoma (SCC) tumors; samples were obtained from patients with locally nonrecurrent and recurrent tumors that had been treated by surgery and radiotherapy. No significant difference was noticed in cyclin A, cyclin B and p34cdc2 expression. However, we noted a significant preferential cytoplasmic location of p34cdc2 in recurring tumors compared to the nonrecurring ones (P < 0.001). This abnormal location of p34cdc2 occurs even in primary tumors in patients with recurring tumors, suggesting that a default in the activation of p34cdc2 kinase could be implicated in clinical radioresistance.

A phase I-II study was initiated in February 1991 of concomitant radiation and cisplatin (CDDP) in the treatment of unresectable head and neck squamous cell carcinomas (n = 12). The first patient was treated palliatively for a cervical recurrence of laryngeal cancer. The 11 other patients had locally advanced (stage IV) previously untreated carcinomas of the oropharynx (n = 9), hypopharynx (n = 1), or cervical node with unknown primary site (n = 1). Standard external radiation was carried out up to a total dose of 60 Gy/6 weeks (7 MeV electron beam) for the first patient and 72 Gy/8 weeks (Co60 beam) for the other 11 patients. CDDP was infused continuously during the entire radiation treatment, 5 days/week. The starting dose was 4 mg/m2/day and was escalated by increments of 1 mg/m2/day; dose-limiting toxicity was observed at 7 mg/m2/day. Neutropenia (grade 4, one patient; grade 3, three patients) and thrombocytopenia (grade 3, one patient; grade 2, one patient) were the limiting factors. Therefore, the recommended dose of CDDP is 6 mg/m2/day. All patients but one completed the scheduled radiation. For the entire group, mucositis was not more severe than that observed with radiotherapy alone. There was no nephro-, oto-, or neurotoxicity. A complete response was obtained in eight (66%) patients. Of these, four were free of disease 12-34 months after completion of treatment and one had a total glossectomy for a tongue necrosis. For the whole series, the mean overall survival was 16 months posttreatment. Pharmacokinetic analysis indicated the total cisplatin accumulation at the end of treatment to be 743-1551 ng/ml. Accumulation of ultrafilterable platin was noted in only one patient (137 ng/ml at the end of treatment).

Purpose: Between November 1988 and May 1992, 14 patients were enrolled in a pilot study to evaluate the feasibility and results of hyperfractionated reirradiation for the treatment of head and neck recurrences or of second primary tumors developed in a previously irradiated volume., Materials and Methods: All patients underwent a surgical resection for the treatment of their recurrence or second cancer. Reirradiation was proposed because of positive margins and/or lymph node metastasis with extra-capsular spread. The planned reirradiation dose was 60 Gy over 5 weeks, with two daily fractions of 1.2 Gy delivered 6-8 hours apart., Results: Of the 14 patients, 10 received the reirradiation scheduled dose (ie, 60 Gy). All patients experienced an acute mucositis that never led to disruption of the treatment. Ten patients died 3 to 41 months after reirradiation (mean: 14 months), three were disease-free 48 to 71 months after reirradiation and one was alive with local progressive disease 74 months after reirradiation. The overall local control rate within the reirradiated volume was 43%. The 24- and 36-month overall survival rates were 50 and 35%, respectively. Overall, 13 late complications were noted: four were grade 1, seven were grade 2, and two were grade 3. Three patients still alive in September 1993 and whose initial files were available were enrolled in an additional study to assess from dose-volume histograms the cumulative doses delivered by the two irradiations., Conclusion: Despite poor local control, reirradiation using a hyperfractionation schedule with high dose level is feasible in terms of acute and late toxicity.

Purpose: To report the final results of a prospective randomized trial that aimed to evaluate efficacy and toxicity of concomitant postoperative radiotherapy and Cisplatin infusion in patients with Stage III or IV squamous cell carcinoma of the head and neck and histological evidence of extracapsular spread of tumor in lymph node metastase(s)., Methods and Materials: Radiotherapy was delivered using a daily dose of 1.7 Gy for the first 54 Gy and 1.8 to 2 Gy until the completion of the treatment. Cisplatin 50 mg i.v. with forced hydratation was given or not every week (i.e., seven to nine cycles) concurrently with radiotherapy. A total of 44 patients were treated by irradiation only (RT group) and 39 by irradiation with chemotherapy (CM group)., Results: The RT group displayed a higher rate of loco-regional failures as compared to CM group (41 vs. 23%; p = 0.08). The overall survival, the survival corrected for deaths by intercurrent disease, and the disease-free survival were better in CM group as compared to RT group with statistically significant differences. Survival without loco-regional treatment failure was better in the CM group, the difference being close to the level of significance (p = 0.05). Survival without distant metastases were comparable in the two therapeutic groups. Ten severe late complications were observed, four in the RT group (17%) and six in the CM group (22%). Cox univariate analysis confirmed the importance of the therapeutic modality in predicting the overall survival, the survival corrected for deaths by intercurrent disease, and the disease-free survival., Conclusions: The present final report of this phase III study confirms preliminary results. The concomitant use of 50 mg weekly Cisplatin infusion and postoperative radiation improved loco-regional control and survival. No significant increase of late radiation complications was observed in the CM group.

Between November 1988 and May 1992, 19 patients were enrolled in a pilot study to evaluate feasibility and results of a hyperfractionated reirradiation in the treatment of head and neck recurrences or second primary tumors developed in previously irradiated volume. Patients were divided in two groups according to the initial treatment before reirradiation: group 1 included 14 patients treated with radical surgery and reirradiated because histological evidence of positive margins and/or extra capsular spread of tumor in lymph node metastases; group 2 included five patients treated with three cycles of CDDP-5FU for unresectable tumors and reirradiated because they experienced a complete or good partial (> or = 80%) response after chemotherapy. The reirradiation planned dose was 60 Gy in 5 weeks, with two daily fractions of 1.2 Gy spaced by 6-8 h intervals. Reirradiation was delivered exclusively with photon beams in 17 cases and with a combination of photon and electron beams in two cases. Follow-up ranged from 3 to 45 months with a median of 17 months. Of the 19 patients, 13 received the reirradiation scheduled dose of 60 Gy. For the six remaining patients, the reirradiation doses ranged from 45.6 to 57.6 Gy. All patients experienced an acute mucositis which never led to interruption of treatment. Of the 14 patients of group 1, 10 died 3-41 months after reirradiation (mean: 14 months), three were disease-free 16-37 months after reirradiation and one patient was alive with local progressive disease 39 months after the reirradiation. The overall local control within reirradiated volume was 36% before and 43% after salvage surgery. For all group 1 patients, 12- and 24-month overall survival was 64 and 36%, respectively (mean: 21 months). All patients of group 2 presented a local failure within the reirradiated volume. Three of them died 12, 16 and 25 months after reirradiation, while two of them were alive with progressive disease 25 and 30 months after reirradiation, respectively. The mean survival was 22 months. Overall, 15 late complications were noted: five grade 1, eight grade 2 and two grade 3. There was no lethal complication. Four patients alive in September 1993, and whose initial technical files were available, were enrolled in an additional study to assess the cumulative doses delivered by the two irradiations. Despite disappointing loco-regional control rates, a reirradiation of 60 Gy using a hyperfractionated schedule is feasible in terms of acute and late toxicity.

Retrospective analysis of detailed patient and tumour factors associated with a complete response to combination inductive chemotherapy with CDDP-5FU (96 or 120 hour continuous infusion) was performed using data from 147 patients with a previously untreated squamous cell carcinoma of the oral cavity, oropharynx or pharyngo-larynx following completion of two (29 patients) or three (118 patients) cycles. Adverse reactions to chemotherapy were documented for all 164 patients included in the study. Eight drug-related deaths occurred due to: acute myocardial infarction (five patients), peptic ulcer disease (two patients) and severe neutropenia with sepsis (one patient). Severe non-lethal complications included marrow depletion (14 patients), peptic ulcer (two patients), thrombophlebitis (seven patients), angina pectoris (two patients), stroke (one patient), pulmonary oedema (one patient) and convulsions (one patient). Six patients refused further treatment because of untoward side effects and tumoral progression was observed in three cases. Separate response rates for the primary site and nodes were determined and analysis of respective predictive factors of response was performed. Complete response was obtained in 31 per cent at the primary site versus 18 per cent for the nodes (p < 0.05). The combined (primary site + nodes) overall complete response rate was 22 per cent. Among 11 factors studied (age, sex, performance status, primary site, tumour differentiation, initial resectability, 5FU dosage per cycle, number of cycles, T, N and TN stages), only performance status, N stage, resectability and number of cycles were associated with a combined complete response. Multivariate analysis showed performance status, N stage, TN stage and resectability to be significant predictive factors of a combined complete response.(ABSTRACT TRUNCATED AT 250 WORDS)