Michel Rives

Induction Chemotherapy Followed by Either Chemoradiotherapy or Bioradiotherapy for Larynx Preservation: The TREMPLIN Randomized Phase II Study

PURPOSE To compare the efficacy and safety of induction chemotherapy (ICT) followed by chemoradiotherapy (CRT) or bioradiotherapy (BRT) for larynx preservation (LP). PATIENTS AND METHODS Previously untreated patients with stage III to IV larynx/hypopharynx squamous cell carcinoma received three cycles of ICT-docetaxel and cisplatin 75 mg/m(2) each on day 1 and fluorouracil 750 mg/m(2) per day on days 1 through 5. Poor responders (< 50% response) underwent salvage surgery. Responders (≥ 50% response) were randomly assigned to conventional radiotherapy (RT; 70 Gy) with concurrent cisplatin 100 mg/m(2) per day on days 1, 22, and 43 of RT (arm A) or concurrent cetuximab 400 mg/m(2) loading dose and 250 mg/m(2) per week during RT (arm B). Primary end point was LP at 3 months. Secondary end points were larynx function preservation (LFP) and overall survival (OS) at 18 months. RESULTS Of the 153 enrolled patients, 116 were randomly assigned after ICT (60, arm A; 56, arm B). Overall toxicity of both CRT and BRT was substantial following ICT. However, treatment compliance was higher in the BRT arm. In an intent-to-treat analysis, there was no significant difference in LP at 3 months between arms A and B (95% and 93%, respectively), LFP (87% and 82%, respectively), and OS at 18 months (92% and 89%, respectively). There were fewer local treatment failures in arm A than in arm B; salvage surgery was feasible in arm B only. CONCLUSION There is no evidence that one treatment was superior to the other or could improve the outcome reported with ICT followed by RT alone (French Groupe Oncologie Radiothérapie Tête et Cou [GORTEC] 2000-01 trial [Induction CT by Cisplatin, 5FU With or Without Docetaxel in Patients With T3 and T4 Larynx and Hypopharynx Carcinoma]). The protocol that can best compare with RT alone after ICT is still to be determined.

Phase III randomized trial of very accelerated radiation therapy compared with conventional radiation therapy in squamous cell head and neck cancer: a GORTEC trial.

PURPOSE With the aim to increase the dose intensity of radiation therapy (RT), and subsequently the locoregional control rate, a very accelerated RT regimen was compared with conventional RT in a series of patients with head and neck squamous cell carcinoma (HNSCC). PATIENTS AND METHODS Between 1994 and 1998, 268 patients with T3 or T4, N0 to N3 HNSCC (staged by 1997 International Union Against Cancer criteria) that was not eligible for surgery were randomly assigned to receive either conventional RT, delivering 70 Gy in 7 weeks to the primary tumor and 35 fractions of 2 Gy over 49 days, or to receive very accelerated RT, delivering 62 to 64 Gy in 31 to 32 fractions of 2 Gy over 22 to 23 days (2 Gy/fraction bid). RESULTS The most common tumor site was the oropharynx and most of the patients (70%) had T4 and N1 to N3 tumors in 72% of patients. The main patient and tumor characteristics were well-balanced between the two arms. The median total doses were 63 Gy (accelerated) and 70 Gy (conventional), with a median overall time of 22 days and 48 days, respectively. Acute mucositis was markedly increased in the accelerated-RT arm (P < .001). The locoregional control rate was improved by 24% at 6 years with accelerated RT. In contrast, disease-free survival and overall survival were not significantly different between the two arms. There was no difference in late effects between the two arms. CONCLUSION The very accelerated RT regimen was feasible and provided a major benefit in locoregional control but had a modest effect on survival.

The Role of Radiation Therapy in Pediatric Mucoepidermoid Carcinomas of the Salivary Glands

OBJECTIVE To investigate the role of radiation therapy in rare salivary gland pediatric mucoepidermoid carcinoma (MEC). STUDY DESIGN A French multicenter retrospective study (level of evidence 4) of children/adolescents treated for MEC between 1980 and 2010 was conducted. RESULTS Median age of the 38 patients was 14 years. Parotid subsite, low-grade, and early primary stage tumors were encountered in 81%, 82%, and 68% of cases, respectively. All except 1 patient were treated by tumoral surgical excision, and 53% by neck dissection (80% of high grades). Postoperative radiation therapy and chemotherapy were performed in 29% and 11% of cases. With a median 62-month follow-up, overall survival and local control rates were 95% and 84%, respectively. There was 1 nodal relapse. Lower grade and early stage tumors had better survival. Postoperative radiation therapy and chemotherapy were associated with similar local rates. Patients with or without prior cancer had similar outcomes. CONCLUSIONS Pediatric salivary gland MEC carries a good prognosis. Low-intermediate grade, early-stage tumors should be treated with surgery alone. Neck dissection should be performed in high-grade tumors. Radiation therapy should be proposed for high grade and/or advanced primary stage MEC. For high-grade tumors without massive neck involvement, irradiation volumes may be limited to the primary area, given the risk of long-term side effects of radiation therapy in children. Pediatric MEC as second cancers retain a similar prognosis. Long-term follow-up is needed to assess late side effects and second cancers.

Brachytherapy in lip carcinoma: long-term results.

PURPOSE The aim of this study was to evaluate the effectiveness of low-dose-rate brachytherapy for local control and relapse-free survival in squamous cell and basal cell carcinomas of the lips. We compared two groups: one with tumors on the skin and the other with tumors on the lip. PATIENTS AND METHODS All patients had been treated at Claudius Regaud Cancer Centre from 1990 to 2008 for squamous cell or basal cell carcinoma. Low-dose-rate brachytherapy was performed with iridium 192 wires according to the Paris system rules. On average, the dose delivered was 65 Gy. RESULTS 172 consecutive patients were included in our study; 69 had skin carcinoma (squamous cell or basal cell), and 92 had squamous cell mucosal carcinoma. The average follow-up time was 5.4 years. In the skin cancer group, there were five local recurrences and one lymph node recurrence. In the mucosal cancer group, there were ten local recurrences and five lymph node recurrences. The 8-year relapse-free survival for the entire population was 80%. The 8-year relapse-free survival was 85% for skin carcinoma 75% for mucosal carcinoma, with no significant difference between groups. The functional results were satisfactory for 99% of patients, and the cosmetic results were satisfactory for 92%. Maximal toxicity observed was Grade 2. CONCLUSIONS Low-dose-rate brachytherapy can be used to treat lip carcinomas at Stages T1 and T2 as the only treatment with excellent results for local control and relapse-free survival. The benefits of brachytherapy are also cosmetic and functional, with 91% of patients having no side effects.

Coregistration of prechemotherapy PET-CT for planning pediatric Hodgkin's disease radiotherapy significantly diminishes interobserver variability of clinical target volume definition.

PURPOSE To assess the interobserver variability in clinical target volume (CTV) definitions when using registered (18)F-labeled deoxyglucose positron emission tomography (FDG-PET-CT) versus side-by-side image sets in pediatric Hodgkins disease (HD). METHODS AND MATERIALS Prechemotherapy FDG-PET-CT scans performed in the treatment position were acquired from 20 children (median age, 14 years old) with HD (stages 2A to 4B) and registered with postchemotherapy planning CT scans. The patients had a median age of 14 years and stages of disease ranging between 2A and 4B. Image sets were coregistered using a semiautomatic coregistration system. The biological target volume was defined on all the coregistered images as a guide to defining the initial site of involvement and to avoid false-positive or negative results. Five radiation oncologists independently defined the CTV for all 20 patients: once using separate FDG-PET-CT images as a guide (not registered) to define CTVa and once using the registered FDG-PET-CT data to define CTVb. The total volumes were compared, as well as their coefficients of variation (COV). To assess the interobserver variability, the percentages of intersection between contours drawn by all observers for each patient were calculated for CTVa and for CTVb. RESULTS The registration of a prechemotherapy FDG-PET-CT scan caused a change in the CTV for all patients. Comparing CTVa with CTVb showed that the mean CTVb increased in 14 patients (range, 0.61%-101.96%) and decreased in 6 patients (range, 2.97%-37.26%). The COV for CTVb significantly decreased for each patient; the mean COVs for CTVa and CTVb were 45% (21%-65%) and 32% (13%-57%), respectively (p = 0.0004). The percentage of intersection among all CTVbs for the five observers increased significantly by 89.77% (1.99%-256.41%) compared to that of CTVa (p = 0.0001). CONCLUSIONS High observer variability can occur during CT-based definition of CTVs for children diagnosed with HD. Registration of FDG-PET and planning CT images resulted in significantly greater consistency of tumor volume definition.

Multimodal treatment and long-term outcome of patients with esthesioneuroblastoma

PURPOSE/OBJECTIVES To analyze the clinical features, treatment modalities and outcome of patients treated for a localized esthesioneuroblastoma (ENB). MATERIALS AND METHODS Forty-three consecutive patients with biopsy proven ENB treated at two referral cancer centers between 1998 and 2010 were retrospectively reviewed. RESULTS 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 (p < 0.0001). 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. CONCLUSION 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.

Stevens–Johnson syndrome after amifostine during radiotherapy

A 52-year-old man presented a cervical lymph node metastasis of squamous cell carcinoma with T0 tongue carcinoma. The patient was treated by cervical lymphadenectomy followed by radiotherapy. For xerostomia prevention, intravenous amifostine 200 mg/m 2 daily was realized 5 days per week, 30 min before each radiotherapy fraction of 2 Gy. Intravenous methylprednisolone 1 mg/kg associated with serotonin 5-HT3 receptor antagonist was also administered during amifostine injection. The other drugs received were topic fungizone and paracetamol with codeine. Fluconazole was given for an oral candidiasis during 10 days 2 weeks before Stevens–Johnson syndrome (SJS). At the end of the fifth week of radiotherapy (at 50 Gy), when the patient had an important radiation-induced localized erythema and mucosal lesions, he presented a bilateral conjunctivitis. Some erythematous macular lesions appeared beyond the irradiated region and 2 days later the patient developed fever. The skin lesions worsened with a skin detachment of the neck, the upper trunk and the face of approximately 9% of the body surface area (Fig. 1). There was also palmar and plantar erythematous papules, perioral lesions, bilateral superficial keratitis and a painful genital erythema. These clinical findings were consistent with SJS. 4 The patient was transferred to the intensive care unit of the burn center. He required ventilation assistance, intravenous antibiotics associated with topical care for skin and oral mucosa and enteral nutrition. A skin biopsy in an intact area at day 5 showed epidermal necrosis with suprabasal cleavage and dermis infiltrate by mononuclear cells without immunoglobulins deposit, consistent with a bullous drug-induced skin reaction. The healing was slow and progressive. Ventilation withdrawal could be realized at day 14. After day 31, a skin graft was realized in 3% of the body surface (neck and ears) with a good engraftment. The patient improved gradually within a total of 8 weeks. The cancer treatment was stopped at 52 Gy instead of the 70 Gy initially planned.

Toxicity and efficacy of cetuximab associated with several modalities of IMRT for locally advanced head and neck cancer

PURPOSE Intensity-modulated radiation therapy (IMRT) has shown its interest for head and neck cancer treatment. In parallel, cetuximab has demonstrated its superiority against exclusive radiotherapy. The objective of this study was to assess the acute toxicity, local control and overall survival of cetuximab associated with different IMRT modalities compared to platinum-based chemotherapy and IMRT in the ARTORL study (NCT02024035). PATIENTS AND METHOD This prospective, multicenter study included patients with epidermoid or undifferentiated nasopharyngeal carcinoma, epidermoid carcinoma of oropharynx and oral cavity (T1-T4, M0, N0-N3). Acute toxicity, local control and overall survival were compared between groups (patients receiving cetuximab or not). Propensity score analysis at the ratio 1:1 was undertaken in an effort to adjust for potential bias between groups due to non-randomization. RESULTS From the 180 patients included in the ARTORL study, 29 patients receiving cetuximab and 29 patients treated without cetuximab were matched for the analysis. Ten patients (34.5%) reported acute dermal toxicity of grade 3 in the cetuximab group versus three (10.3%) in the non-cetuximab group obtained after matching (P=0.0275). Cetuximab was not significantly associated with more grade 3 mucositis (P=0.2563). There were no significant differences in cutaneous or oral toxicity for patients treated with cetuximab between the different IMRT modalities (P=1.000 and P=0.5731, respectively). There was no significant difference in local relapse-free survival (P=0.0920) or overall survival (P=0.4575) between patients treated with or without cetuximab. CONCLUSION Patients treated with cetuximab had more cutaneous toxicities, but oral toxicity was similar between groups. The different IMRT modalities did not induce different toxicity profiles.

Very accelerated radiotherapy or concurrent chemoradiotherapy for N3 head and neck squamous cell carcinoma: Pooled analysis of two GORTEC randomized trials

OBJECTIVE To analyze the outcome of N3 patients treated with very accelerated radiotherapy (VART) or different schedules of concurrent chemoradiotherapy (CRT) within two phase III trials. PATIENTS AND METHODS Data of 179 patients with N3 HNSCC from two GORTEC randomized trials (96-01 and 99-02) were pooled. Patients received either VART: 64.8Gy/3.5weeks or one of the 3 following CRT regimens: Conventional CRT: 70Gy/7weeks+3 cycles carboplatin-5FU; Moderately accelerated CRT: 70Gy/6weeks+2 cycles carboplatin-5FU; Strongly intensified CRT: 64Gy/5weeks+cisplatin (days 2, 16, 30) and 5 FU (days 1-5, 29-33) followed by 2 cycles adjuvant cisplatin-5FU. RESULTS Median follow-up was 13.3 and 5.2years for GORTEC 96-01 and GORTEC 99-02, respectively. Five-year overall survival (OS) was 13.8%. No significant difference was observed between CRT versus VART in terms of OS (hazard ratio [HR]: 0.93, p=0.68), loco-regional progression (HR: 0.70, p=0.13), or distant progression (HR: 0.86, p=0.53). OS was worse for patients with T3-4 tumors versus early T stage (11.0% versus 25.7%, p=0.015). In multivariate analysis, the oropharyngeal subsite presented a higher risk of distant metastasis (as first event 46.5% vs 19.2%, p<0.001),). A significant interaction between treatment modalities and subsites has been observed concerning loco-regional and distant failures. CONCLUSION The outcome of N3 HNSCC was extremely poor despite treatment intensification and no difference between CRT and VART. Both distant metastases and loco-regional failures remain important treatment challenge.

Clinical characteristics and prognostic factors of sinonasal undifferentiated carcinoma: a multicenter study: Management of SNUC: the REFCOR experience

Sinonasal undifferentiated carcinoma (SNUC) is a very rare entity with a poor prognosis. Due to the lack of studies on the subject, evidence is lacking concerning its management.