Bernard Coche-Dequeant

Post-radiation severe xerostomia relieved by pilocarpine: a prospective French cooperative study.

BACKGROUND AND PURPOSE The aim of the study was: (1) to confirm the action of pilocarpine hydrochloride (Salagen) against xerostomia: (2) to correlate the response to dose/volume radiotherapy parameters. MATERIALS AND METHODS From June 1995 to February 1996, 156 patients with severe radiation induced xerostomia received pilocarpine hydrochloride orally. IS mg per day with a 5 mg optional increase at S weeks up to a daily dose of 25 mg beyond 9 weeks. RESULTS One hundred and forty five patients are fully evaluable. Treatment compliance was 75%. Thirty eight patients (26%) stopped treatment before week 12 for acute intolerance (sweating, nausea, vomiting) or no response. No severe complication occurred. Ninety ses en patients (67%) reported a significant relief of symptoms of xerostomia at 12 weeks. Within 12 weeks, the size of the subgroup ith normal food intake almost doubled (13-24 patients) while the size of the subgroup with (nearly) impossible solid food ingestion decreased by 38% (47 vs. 29 patients). The impact on quality of life was considered important or very important by 77% of the responders. CONCLUSIONS No difference was found according to dose/volume radiotherapy parameters suggesting that oral pilocarpine hydrochloride: (1) acts primarily by stimulating minor salivary glands: (2) can be of benefit to patients suffering of severe xerostomia regardless of radiotherapy dose/volume parameters: (3) all responders are identified at 12 weeks.

Cervical lymph nodes from an unknown primary tumor in 190 patients

Over 10 years, 475 patients with isolated lateral neck masses were evaluated: 190 with lymph nodes from an unknown primary tumor (LNUP), 188 with neck lymphomas, 78 with benign tumors, 10 with sarcomas, and 9 with chemodectomas. This study focused on the patients with LNUP. Only 86 patients were treated with surgery (plus radiotherapy). Other patients were treated with radiotherapy (84) or chemotherapy (13) or had no treatment (7). For the overall population, failures in the neck occurred in 51% of the patients and distant metastases in 27%, while primary tumors appeared in 16%. Survival rates at 3, 5, and 10 years were 27%, 19%, and 7%, respectively, for the overall population and 45%, 35%, and 19%, respectively, for the surgical group. The diagnosis and therapeutic approach had a direct effect on neck control; failure in the neck occurred in 7 of 47 patients (15%) when fine needle aspiration and radical neck dissection with radiotherapy were performed, in 5 of 12 patients (42%) when fine needle aspiration and modified neck dissection with radiotherapy were used, in 5 of 12 patients (42%) when adenectomy diagnosis and radiotherapy treatment were performed, and in 6 of 11 patients (54%) when diagnosis by incisional biopsy was performed prior to admission, despite subsequent radical neck dissection and radiotherapy treatment. In our opinion, panendoscopy and fine needle aspiration should be the first-line diagnostic approach. When cytologic diagnosis proves impossible, the second-line approach must consist of cervical exploration with frozen section examination and excisional biopsy, followed by immediate appropriate treatment. In cases of LNUP, radical neck dissection seems to be preferable.

Multi institutional phase II study of concomitant stereotactic reirradiation and cetuximab for recurrent head and neck cancer.

PURPOSE Recurrent head and neck cancer is associated to a poor survival prognosis. A high toxicity rate is demonstrated when surgery and/or radiotherapy and/or chemotherapy are combined. Furthermore, the duration of treatment is often not ethically compatible with the expected survival (median survival<1year). Normal tissues tolerance limits the use of reirradiation and stereotactic body radiotherapy (SBRT) could offer precise irradiation while sparing healthy tissues. After completion of a feasibility study, results of a multicentric study (Lille, Nancy & Nice) using SBRT with cetuximab are reported. The aim of the study was to deliver non toxic short course SBRT (2weeks) in order to get the same local control as the one demonstrated with longer protocols. METHODS AND MATERIALS Patients with inoperable recurrent, or new primary tumor in a previously irradiated area, were included (WHO<3). Reirradiation (RT) dose was 36Gy in six fractions of 6Gy to the 85% isodose line covering 95% of the PTV with 5 injections of concomitant cetuximab (CT). All patients had previous radiotherapy, 85% had previous surgery and 48% previous chemotherapy. RESULTS Between 11/2007 and 08/2010, 60 were included (46 men and 14 women), 56 received CT+RT, 3 were not treated and 1 received only CT. Median age was 60 (42-87)) and all 56 patients had squamous carcinoma and received concomitant cetuximab. Mean time between previous radiotherapy and the start of SBRT was 38months. Cutaneous toxicity was observed for 41 patients. There was one toxic death from hemorrhage and denutrition. Median follow-up was 11.4months. At 3months, response rate was 58.4% (95% CI: 43.2-72.4%) and disease control rate was 91.7% (95% CI: 80.0-97.7%). The one-year OS rate was 47.5% (95% CI: 30.8-62.4). CONCLUSION These results suggest that short SBRT with cetuximab is an effective salvage treatment with good response rate in this poor prognosis population with previously irradiated HNC. Treatment is feasible and, with appropriate care to limiting critical structure, acute toxicities are acceptable. This combination may be the reference treatment is this population.

Salvage Stereotactic Reirradiation With or Without Cetuximab for Locally Recurrent Head-and-Neck Cancer: A Feasibility Study

PURPOSE Normal tissues tolerance limits the use of reirradiation for recurrent head-and-neck cancers (HNC). Stereotactic body radiotherapy (SBRT) could offer precise irradiation while sparing healthy tissues. Results of a feasibility study using SBRT with or without cetuximab are reported for reirradiation of recurrent primary HNC. METHODS AND MATERIALS Patients with inoperable recurrent, or new primary tumor, in a previously irradiated area were included. Reirradiation dose was 36 Gy in six fractions of 6 Gy to the 85% isodose line covering 95% of the planning target volume. Patients with squamous cell carcinoma received concomitant cetuximab. RESULTS Between June 2007 and January 2010, 40 patients were prospectively treated for 43 lesions. Median age was 60 and median tumor size was 29 mm. Fifteen patients received concomitant cetuximab and 1 received concomitant cisplatin. Median follow-up was 25.6 months with 34 patients evaluable for tumor response. Median overall survival was 13.6 months and response rate was 79.4% (15 complete and 12 partial responses). Grade 3 toxicity occurred in 4 patients. CONCLUSION These results suggest that short SBRT with or without cetuximab is an effective salvage treatment with good response rate in this poor prognosis population with previously irradiated HNC. Treatment is feasible and, with appropriate care to limiting critical structure, acute toxicities are acceptable. A prospective multicenter Phase II trial of SRT and concomitant cetuximab in recurrent HNC squamous cell carcinoma is ongoing.

Comparison of surgery and radiotherapy in T1 and T2 glottic carcinomas

We retrospectively studied 356 patients who received treatment for T1 and T2 glottic carcinomas. Two hundred and thirty patients were treated with surgery (200 by cordectomy, 15 by vertical partial laryngectomy, and 15 by subtotal laryngectomy). Radiotherapy was used to treat 126 patients. There were 206 T1 and 24 T2 lesions in the surgically treated group and 107 T1 and 19 T2 lesions in the radiotherapy group. Sixty-four patients received radiotherapy because it was the treatment of choice (scheduled radiotherapy) and 62 patients received radiotherapy because they had medical contraindications for surgery (default radiotherapy). Actuarial survival rates at 5 years were 84% for patients who underwent surgery and 78% for patients who underwent scheduled radiotherapy. In the surgically treated group, there were 10 local recurrences in 170 patients with tumors of the true vocal cord, eight recurrences in 36 patients with anterior commissure lesions, and 6 recurrences in 24 patients with tumors extending to the arytenoid. In the scheduled radiotherapy group, there were 7 local recurrences in 38 patients with true vocal cord tumors, 6 recurrences in 20 patients with anterior commissure tumors, and 5 recurrences in 6 patients with tumors extending to the arytenoid. We conclude that survival is similar in these patients whether they receive operative treatment or scheduled radiotherapy. However, in the radiotherapy group, local recurrences were more frequent in patients with tumors extending to the arytenoid. We advocate extended functional surgery for patients with T1 and T2 glottic lesions except for those with small tumors arising from the middle third of the vocal cord.

CONCOMITANT B.I.D. RADIOTHERAPY AND CHEMOTHERAPY WITH CISPLATIN AND 5-FLUOROURACIL IN UNRESECTABLE SQUAMOUS-CELL CARCINOMA OF THE PHARYNX: CLINICAL AND PHARMACOLOGICAL DATA OF A FRENCH MULTICENTER PHASE II STUDY

PURPOSE The aim of this phase II study conducted on unresectable squamous cell carcinoma (USCC) of the oro- and hypopharynx was to associate twice-a-day (b.i.d.) continuous nonaccelerated radiotherapy with concomitant cisplatin (CP)-5-fluorouracil (5-FU) chemotherapy, both given at full dose. Feasibility, efficacy, survival, and pharmacokinetic-pharmacodynamic relationships were analyzed. METHODS AND MATERIALS Fifty-four consecutive patients with strictly USCC of oro- and/or hypopharynx received continuous b.i.d. radiotherapy (RT) (2 daily fractions of 1.2 Gy, 5 days a week, with a 6-h minimal interval between fractions). Total RT dose was 80.4 Gy on the oropharynx and 75.6 Gy on the hypopharynx. Three chemotherapy (CT) courses of CP-5-FU were given during RT at 21-day intervals (third not delivered after the end of RT). CP dose was 100 mg/m2 (day 1) and 5-FU was given as 5-day continuous infusion (day 2-day 6: 750 mg/m2/day cycle 1, 750 mg total dose/day cycle 2 and 3). Pharmacokinetics was performed for 5-FU (105 h follow-up) and CP (single sample at 16 h). Special attention was paid to supportive care. RESULTS Good feasibility of RT was observed (85.2% of patients with total dose > 75 Gy). Five patients received 1 CT cycle, 34: 2 cycles, and 15: 3 cycles. The most frequent and severe acute toxicities were mucositis with grade 3-4 occurring in 28% at cycle 1 and 86% at cycle 2, as well as neutropenia (43% at cycle 2). Locoregional control at 6 months was observed in 66.7% of patients. No late toxicity above grade 2 RTOG was noticed. CP dose and 5-FU AUC(0-105h) were significantly linked to grade 3-4 neutropenia (cycle 2). Cumulative total platinum (Pt) concentration and Karnofsky index were the only independent predictors of locoregional control at 6 months. Finally, total RT dose and total Pt concentration were the only independent predictors of specific survival. CONCLUSION This protocol showed good locoregional response with an acceptable toxicity profile. Pharmacokinetic survey is probably an effective approach to further reduce toxicity and improve efficacy. A multicentric randomized phase III study, now underway, should confirm these encouraging results.

MRI definition of target volumes using fuzzy logic method for three-dimensional conformal radiation therapy.

PURPOSE Three-dimensional (3D) volume determination is one of the most important problems in conformal radiation therapy. Techniques of volume determination from tomographic medical imaging are usually based on two-dimensional (2D) contour definition with the result dependent on the segmentation method used, as well as on the users manual procedure. The goal of this work is to describe and evaluate a new method that reduces the inaccuracies generally observed in the 2D contour definition and 3D volume reconstruction process. METHODS AND MATERIALS This new method has been developed by integrating the fuzziness in the 3D volume definition. It first defines semiautomatically a minimal 2D contour on each slice that definitely contains the volume and a maximal 2D contour that definitely does not contain the volume. The fuzziness region in between is processed using possibility functions in possibility theory. A volume of voxels, including the membership degree to the target volume, is then created on each slice axis, taking into account the slice position and slice profile. A resulting fuzzy volume is obtained after data fusion between multiorientation slices. Different studies have been designed to evaluate and compare this new method of target volume reconstruction and a classical reconstruction method. First, target definition accuracy and robustness were studied on phantom targets. Second, intra- and interobserver variations were studied on radiosurgery clinical cases. RESULTS The absolute volume errors are less than or equal to 1.5% for phantom volumes calculated by the fuzzy logic method, whereas the values obtained with the classical method are much larger than the actual volumes (absolute volume errors up to 72%). With increasing MRI slice thickness (1 mm to 8 mm), the phantom volumes calculated by the classical method are increasing exponentially with a maximum absolute error up to 300%. In contrast, the absolute volume errors are less than 12% for phantom volumes calculated by the fuzzy logic method. On radiosurgery clinical cases, target volumes defined by the fuzzy logic method are about half of the size of volumes defined by the classical method. Also, intra- and interobserver variations slightly decrease with the fuzzy logic method, resulting in the definition of a better common volume fraction. CONCLUSION Our fuzzy logic method shows accurate, robust, and reproducible results on phantoms and clinical targets imaged on MRI.

Management of early oral cavity cancer. Experience of Centre Oscar Lambret

From 1974 to 1983, 579 patients presenting with early oral cancer (excluding lip tumours) were treated at Centre Oscar Lambret. Of these, 429 were treated locally by brachytherapy with local control achieved in 82% of the cases (90% after salvage surgery). Treatment-related complications occurred in 19% of the cases, requiring surgical management in 13 patients. In contrast, only 51% of the 35 patients treated by external radiotherapy and brachytherapy were controlled, resulting in a poor 5-year survival (14%). Results for the 24 patients treated surgically were similar to those of brachytherapy alone. Finally, for T1 T2 N0 patients, the advantages of an elective neck dissection are not clear and could be clarified by a randomised trial. Indeed, this retrospective study failed to find a significant difference in the incidence of death due to an uncontrolled neck evolution whatever the neck management.

La cellule de retour d’expérience (CREx) en radiothérapie : un outil indispensable au management de la sécurité. Une évaluation après deux ans d’activité au centre Oscar-Lambret

After working on treatment organisation in radiotherapy (bonne pratiques organisationnelles en radiothérapie - action pilote MEAH 2003), the development of a security policy has become crucial. With the help of Air France Consulting and the MEAH, three cancer centers in Angers, Lille and Villejuif worked together on the implantation of experience feed back committees (CREx) dedicated to the registration, analysis and correction of precursor events. After two years, we report the centre Oscar-Lambret experience in Lille and try to get the recommendations for generalisation of the process. This seems now to be compulsory for security management in oncology.

Treatment of laryngeal cancer: the permanent challenge

There are many options to treat larynx cancers. Throughout the 20th century, surgical research has provided many partial surgery techniques (either open surgery or endoscopic CO2 surgery). In parallel, the modification of radiotherapy schedules has notably improved the local control with definitive irradiation. The appearance of active chemotherapy regimens has also modified the concept of treatment for advanced disease, allowing a decrease in the total indications of laryngectomy, although this remains the treatment of choice in some cases. The selection of the most appropriate treatment is based on a multidisciplinary approach. Early diseases may be treated by open surgery, endoscopic laser CO2 surgery or irradiation. Some advanced diseases may be treated by partial surgery, but the majority are theoretically candidates for radical surgery when resectable. In many instances, but not in all, chemotherapy-based larynx-preserving protocols may avoid performing such mutilating surgery. When inoperable, larynx cancers are better treated by combined chemotherapy and irradiation when the performance status of the patient is compatible with such an intensive regimen.