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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.

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.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.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.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).

Background and purpose To report the long-term results after definitive radiotherapy (RT) for pyriform sinus squamous cell carcinoma (SCC). Material and methods The data concerning all patients treated for pyriform sinus SCC with RT with a curative intent between 1990 and 2006 were reviewed. Results A total of 249 patients were included. The median follow-up is 6.5years. Overall 123 patients had relapsed. For the entire population, the 5-year local control, regional control, freedom-from-distant metastasis, and overall survival rate were 68%, 69%, 78% and 38%, respectively. The 5-year local control rate for the 107 T1–T2 tumors was 85% (95% confidence interval (CI): 75–91). N stage was the main risk factor for the development of distant metastases, with a hazard ratio of 8.9 (95% CI: 2.1–39) and 15.6 (95% CI: 3.6–67.8) for N2 and N3 patients respectively. For patients with N2–N3 disease, pre-RT neck dissection improved regional control but not overall survival. Moderate to severe late complications occurred in 50 patients (28% of the patients without local relapse). Conclusion A high local control rate can be achieved when treating T1–T2 hypopharynx cancers with definitive radiotherapy. The high rate of nodal and distant relapses among patients with N2–N3 disease warrants intensification of therapy.

SummaryIntensity-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.

The variation in the risk of solid second malignant neoplasms (SMN) with time since first cancer during childhood has been previously reported. However, no study has been performed that controls for the distribution of radiation dose and the aggressiveness of past chemotherapy, which could be responsible for the observed temporal variation of the risk. The purpose of this study was to investigate the influence of the treatment on the long-term pattern of the incidence of solid SMN after a first cancer in childhood. We studied a cohort of 4400 patients from eight centres in France and the UK. Patients had to be alive 3 years or more after a first cancer treated before the age of 17 years and before the end of 1985. For each patient in the cohort, the complete clinical, chemotherapy and radiotherapy history was recorded. For each patient who had received external radiotherapy, the dose of radiation received by 151 sites of the body were estimated. After a mean follow-up of 15 years, 113 children developed a solid SMN, compared to 12.3 expected from general population rates. A similar distribution pattern was observed among the 1045 patients treated with radiotherapy alone and the 2064 patients treated with radiotherapy plus chemotherapy; the relative risk, but not the excess absolute risk, of solid SMN decreased with time after first treatment; the excess absolute risk increased during a period of at least 30 years after the first cancer. This pattern remained after controlling for chemotherapy and for the average dose of radiation to the major sites of SMN. It also remained when excluding patients with a first cancer type or an associated syndrome known to predispose to SMN. When compared with radiotherapy alone, the addition of chemotherapy increases the risk of solid SMN after a first cancer in childhood, but does not significantly modify the variation of this risk during the time after the first cancer. © 1999 Cancer Research Campaign

The biological rationale for fractionated radiotherapy treatment and the development of noninvasive head fixation systems have led to the increased use of fractionated stereotactic irradiation for intracranial lesions, especially with curative intent. The authors present an overview of the most common immobilization systems with special reference to the evaluation procedures to determine the precision of repositioning. For the different noninvasive head fixation systems used to perform stereotactic fractionated treatments and for several setups, the repositioning accuracy reported is ±1 mm. The maximal displacement observed, 2.3 mm, indicates that these frame types are not suitable for single-fraction treatment. Numerical data are discussed. Finally, the different quality assurance procedures required to perform fractionated stereotactic irradiation are analyzed.

The goal of the present work was to compare outcomes of definitive concurrent cisplatin-based chemoradiotherapy (CRT) with cetuximab-based bioradiotherapy (BRT) in locally advanced head-and-neck squamous cell carcinoma (HNSCC). Between 2006 and 2012, 265 patients with locally advanced HNSCC were treated at our institution with CRT (n = 194; 73 %) with three cycles of cisplatin (100 mg/m2, every 3 weeks) or BRT (n = 71; 27 %) with weekly cetuximab. Patients receiving BRT had more pre-existing conditions (Charlson index ≥ 2) than the CRT group (p = 0.005). Median follow-up was 29 months. In all, 56 % of patients treated with CRT received the planned three cycles (92 % at least two cycles) and 79 % patients treated with BRT received six cycles or more. The 2-year actuarial overall survival (OS) and progression-free survival (PFS) were 72 % and 61 %, respectively. In the multivariate analysis (MVA), T4 stage, N2–3 stage, smoking status (current smoker as compared with never smoker), and non-oropharyngeal locations predicted for OS, whereas BRT association with OS was of borderline significance (p = 0.054). The 2-year actuarial locoregional control (LRC) and distant control (DC) rates were 73 and 79 %, respectively. CRT was independently associated with an improved LRC (2-year LRC: 76 % for CRT vs. 61 % for BRT) and DC (2-year LRC: 81 % for CRT vs. 68 % for BRT) in comparison with BRT (p

To analyze the clinical features, treatment modalities and outcome of patients treated for a localized esthesioneuroblastoma (ENB).Forty-three consecutive patients with biopsy proven ENB treated at two referral cancer centers between 1998 and 2010 were retrospectively reviewed.Overall, 5 patients had stage A disease, 13 stage B, 16 stage C and 9 stage D according to the modified Kadish classification. Neo-adjuvant chemotherapy was performed in 23 patients leading to a 74 % response rate. Thirty-one patients were treated by surgery. Thirty-nine patients (90.6%) underwent radiation therapy. Twelve patients received bilateral cervical lymph node irradiation (LNI). After a median follow-up of 77 months, the 5-year overall and progression free survival were 65% and 57%. Twelve patients (28%) had a locoregional relapse leading to 10 ENB-related deaths. The major prognostic factor was the modified Kadish stage with a 3-year survival for stage A-B, C and D of 100%, 48% and 22% respectively (p0.0001). Two (9%) isolated cervical lymph node relapses occurred among staged B and C patients treated without elective LNI and none after elective or adjuvant LNI.The high risk of locoregional failure in ENB justifies the use of multimodal therapy. Induction chemotherapy leads to a high response rate. Elective LNI might prevent regional failure in locally advanced disease.

Summary 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.

In this study we report on the use of two non-invasive head frames in fractionated stereotactic irradiation for small benign or low grade brain tumors. Sixty-one patients were treated from April 1988 to December 1992 with external stereotactic irradiation: 12 presented with arteriovenous malformations (AVMs), 32 with benign tumors, and 17 with malignant tumors. Sire of the lesions ranged from 15 to 45 mm in diameter. Two immobilization devices were used: the Laitinen stereoadapter, until December 1992, and then the Beverly frame, specifically designed for radiotherapy. Treatment was given daily, 5 days/week, using 1 or 2 non-coplanar arcs, the dose per fraction ranging from 2 to 3 Gy. The study of the accuracy of the two frames showed an average discrepancy

Radiation-induced optic neuropathy (RION) is a late complication of radiotherapy, resulting in severe visual loss.1 We report a RION case following radiation therapy delivered at a dose widely considered as innocuous, occurring on a background of previous isolated optic neuritis. Increased brain sensitivity to radiation has been observed in patients with multiple sclerosis (MS),2–4 but we are not aware of previously reported cases solely involving the optic nerves (ONs). This aspect deserves consideration when defining therapeutic strategies.

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 5 years. 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 1 year, NS). Sixteen patients experienced clinical grade ⩾3 late toxicities (>6 months), 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.

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 Radiotherapie Tete 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.

Purpose To determine the maximum tolerated dose (MTD) of oral cisplatin (CP Ethypharm®) in combination with radiotherapy in head and neck squamous cell carcinoma (HNSCC) and the recommended dose for phase II trials. Patients and methods Phase I, multicenter, open-labelled, non-comparative and dose escalating trial. CP Ethypharm® was administered on five consecutive days every other week for 7weeks (4 treatment cycles) in combination with radiotherapy. Eighteen patients with locally advanced HNSCC were allocated to four cisplatin dose levels: 10mg/m 2 /day: 4 patients; 15mg/m 2 /day: 4, 20mg/m 2 /day: 5 and 25mg/m 2 /day: 5. The inclusion of patients was dictated by occurrence of dose limiting toxicities (DLTs) at each dosing level. Results The most frequently experienced AEs were gastrointestinal (GI) disorders. Five DLTs were observed, including three at 25mg/m 2 level (two grade 2 renal toxicities, one grade 3 GI and renal toxicities), one at 20mg/m 2 level (grade 3 GI disorders), one at 10mg/m 2 level (grade 4 mucositis). PK analysis showed no significant difference of C max values between day 1 and day 5 of treatment at each dose level (total & ultrafilterable platinum). Conclusion Due to 3 DLTs experienced at 25mg/m 2 /day, MTD was reached and the recommended dose for phase II studies was determined as 20mg/m 2 /day.

Purpose To assess the specific role of treatment and type of first cancer (FC) in the risk of long-term subsequent breast cancer (BC) among childhood cancer survivors. Patients and Methods In a cohort of 1,814 3-year female survivors treated between 1946 and 1986 in eight French and English centers, data on chemotherapy and radiotherapy were collected. Individual estimation of radiation dose to each breast was performed for the 1,258 patients treated by external radiotherapy; mean dose to breast was 5.06 Gy (range, 0.0 to 88.0 Gy) delivered in 20 fractions (mean). Results Mean follow-up was 16 years; 16 patients developed a clinical BC, 13 after radiotherapy. The cumulative incidence of BC was 2.8% (95% CI, 1.0% to 4.5%) 30 years after the FC and 5.1% (95% CI, 2.1% to 8.2%) at the age of 40 years. The annual excess incidence increased as age increased, whereas the standardized incidence ratio decreased. On average, each Gray unit received by any breast increased the excess relative risk of BC by 0.13 (< 0.0 to 0.75). After stratification on castration and attained age, and adjusting for radiation dose, FC type, and chemotherapy, a higher risk of a subsequent BC was associated with Hodgkin’s disease (relative risk, 7.0; 95% CI, 1.4 to 30.9). Conclusion The reported high risk of BC after childhood Hodgkin’s disease treatment seems to be due not only to a higher radiation dose to the breasts, but also to a specific susceptibility.

Purpose: In order to provide more information for the clinician and to analyze the impact of radiation therapy on the loco-regional disease-free interval (LRFI), disease-free interval (DFI) and specific overall survival (OS), a multicentric retrospective study of uterine sarcomas has been undertaken using cases reported to the Grup Oncologic Catala-Occita (GOCO). Patients and Methods: One hundred three patients were selected for this study with a median follow-up period of 49 months. Patients were restaged using the FIGO classification for endometrial adenocarcinoma. Radiotherapy was administered postoperatively to the entire pelvis in 52% of cases (54/103) and was combined with brachytherapy in 24 patients. Mean given dose was 48 Gy, with a 95% confidence interval of 45 to 50 Gy. Variables have been tested for homogeneity between hospitals. Univariate and multivariate analyses have also been carried out. Results: Mean age of the selected patients was 59 years (range 35–84). Stages were distributed as follows: 66 patients (64%) in Stage I; 16 in Stage II (15.5%); 12 in Stage III (11.5%); 9 patients in Stage IVa (9%). Pathological distribution was 41.5% leiomyosarcoma, 39% mixed Mullerian tumours, 16.5% stromal sarcomas, and 2.9% of a miscellaneous group. Overall survival for the entire group was 63.7% and 56% at 2 and 5 years, respectively. Probability of LRFI reached 59.8% at 2 years and 57.4 at 5 years. The DFI at 2 and 5 years were 52.9% and 48.7%, respectively. The LRFI probability was 41% and 36% at 2 and 5 years, respectively, without radiotherapy and reached 76% at 2 and 5 years among those patients treated with radiotherapy. There was also an increase in DFI probability because of the effect of radiotherapy, from 35% to 68.5% and from 33% to 53% at 2 and 5 years, respectively. The overall survival probability for patients treated with radiotherapy was 76% and 73% at 2 and 5 years, respectively and 51% at 2 years and 37% at 5 years without radiotherapy. Multivariate analysis demonstrated that radiotherapy improved LRFI, DFI, and overall survival. Conclusion: We conclude that postoperative radiotherapy in our series of patients diagnosed with uterine sarcoma has an impact on loco-regional and disease-free progression intervals and survival.

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.