Combined analysis of MGMT methylation and dynamic-susceptibility-contrast MRI for the distinction between early and pseudo-progression in glioblastoma patients.

INTRODUCTION: Currently, no single diagnostic modality allows the distinction between early progression (EP) and pseudo-progression (Psp) in glioblastoma patients. Herein we aimed to identify the characteristics associated with EP and Psp, and to analyze their diagnostic value alone and in combination. MATERIAL AND METHODS: We reviewed the clinical, conventional magnetic resonance imaging (MRI), and molecular characteristics (MGMT promoter methylation, IDH mutation, and EGFR amplification) of glioblastoma patients who presented an EP (n=59) or a Psp (n=24) within six months after temozolomide radiochemotherapy. We analyzed relative cerebral blood volume (rCBV) and relative vessel permeability on K2 maps (rK2) in a subset of 33 patients using dynamic-susceptibility-contrast MRI. RESULTS: In univariate analysis, EP was associated with neurological deterioration, higher doses of dexamethasone, appearance of a new enhanced lesion, subependymal enhancement, higher rCBV and rK2 values. Psp occurred earlier after radiotherapy completion and was associated with IDH1 R132H mutation, and MGMT methylation. In multivariate analysis, rCBV, rK2, and MGMT methylation status were independently associated with EP and Psp. All patients with a methylated MGMT promoter and a low rCBV (<1.75) were classified as Psp while all patients with an unmethylated MGMT promoter and a high rCBV (≥1.75) were classified as EP. Among patients with discordant MGMT methylation and rCBV characteristics, higher rK2 values tended to be associated with EP. CONCLUSION: Combined analysis of MGMT methylation, rCBV and vessel permeability on K2 maps seems helpful to distinguish EP from Psp. A prospective study is warranted to confirm these results.

[Radiotherapy of chloroma or granulocytic sarcoma: A literature review]. / Radiothérapie des chloromes ou sarcomes granulocytiques: revue de la littérature.

Granulocytic sarcoma, or chloroma, is a rare clinical entity, usually associated with a blood disease, including acute myeloid leukemia. Management strategies are based on the combination of systemic therapy and local therapy (surgery or radiation). Data for radiotherapy dose are derived from retrospective studies and case reports. We conducted a literature review using the Pubmed search engine to clarify the terms and indications for radiotherapy of chloromas.

Patterns of care and survival of glioblastoma patients: a comparative study between 2004 and 2008 in Lyon, France.

INTRODUCTION: The treatment of glioblastomas (GBMs) has changed significantly since 2005. However, the extent to which this change has improved overall survival (OS) of patients treated outside clinical trials remains to be determined. METHODS: We compared the patterns of care and OS of all GBM patients diagnosed in 2004 (n=105) and in 2008 (n=130) in our center. RESULTS: Younger patients (aged<70 years) diagnosed in 2008 received temozolomide radiochemotherapy as the initial treatment and bevacizumab at recurrence more frequently than those diagnosed in 2004 (69% vs 26% P<10(-4) and 41% vs 3%, P<10(-4), respectively). Elderly patients (aged≥70 years) diagnosed in 2008 received an oncological treatment (radiotherapy and/or chemotherapy) more frequently than those diagnosed in 2004 (67% vs 38%, P=0.006). The patients diagnosed in 2008 had longer OS than those diagnosed in 2004 (10.5 months vs 5.3 months, P=0.001). This finding was true for both younger and elderly patients (15.3 months vs 8.9 months, P=0.02 and 6.4 months vs 3.2 months, P=0.0002, respectively) and when considering only IDH1 wild-type patients (8.9 months vs 5.3 months, P=0.004). CONCLUSION: In our center, the change in the patterns of care for GBMs between 2004 and 2008 has been associated with a significant improvement in OS.

[Dosimetric impact of breath-hold in the treatment of hepatocellular carcinoma by conformal radiation therapy]. / Impact dosimétrique du blocage respiratoire dans le traitement du carcinome hépatocellulaire par irradiation de conformation.

OBJECTIVE: To evaluate the dosimetric impact of breath-hold during radiotherapy of hepatocellular carcinoma (HCC) and to determinate the optimal respiratory phase for treatment (exhale or inhale). PATIENTS AND METHODS: Two CT scans were performed in inhale and in exhale in 20 patients with HCC. The GTV was delineated slice by slice on the inspiration breath hold acquisition (GTV(insp)) and on the expiration breath hold acquisition (GTV(exp)). The superposition of two GTV allowed to obtain the global GTV (free respiration). PTV was defined by adding a margin of 1cm around each GTV. The liver, the duodenum, the two kidneys, the stomach and the spinal cord were delineated on each acquisition as organs at risk (OAR). Three dosimetric plans were created on inspiration, expiration and on global PTV. RESULTS: The mean reduction in the volume of PTV with conformal radiation therapy (3D-CRT) in the hold-breath group compared to the free respiration group was of 33.5+/-11.9%. The average difference of V50%, V20, V30, V40 and V50 were around 4% in favor of the breath hold. The average value of NTCP was 8.9% in free respiration, 4.5% in expiration and 3.2% in inspiration. Further improvement in the OARs dosimetric parameters for the breath hold was observed. CONCLUSION: Compared to the conformal radiotherapy with free respiration, the breath-hold allows reducing the volume of the PTV and the doses to the healthy liver and organs at risk. The use of this modality during different radiotherapy techniques (3D-CRT, IMRT and stereotactic) may be recommended. No difference in dosimetric value has been observed between the breath hold in expiratory and inspiratory phases.

[Irradiation of hepatocellular carcinoma: impact of breathing on motions and variations of volume of the tumor, liver and upper abdominal organs]. / L'irradiation des carcinomes hépatocellulaires: impact de la respiration sur les mouvements et variations de volume de la tumeur, du foie et des organes intra-abdominaux.

PURPOSE: To evaluate the amplitude of motion and the variations of volume of the tumor, the liver and upper abdominal organs induced by breathing during the irradiation of hepatocellular carcinoma (HCC). MATERIAL AND METHODS: Two scanners were performed in inhale and in exhale not forced in 20 patients with a HCC. The liver (left/right lobes), the tumor, the duodenum, the two kidneys and the pancreas were delineated on each acquisition. The superposition of the two spirals made it possible to measure the displacements and variations of volume of these structures in the craniocaudal (CC), lateral (Lat), and anteroposterior (AP) directions. RESULTS: The mean displacement of the tumour in CC, Lat and AP was of 19.7+/-8.3 mm, 4.5+/-2.3 mm, and 8.9+/-6.5 mm. The greatest amplitude of movement was obtained in CC for the right and left hepatic lobes (19+/-6.5 mm, 10+/-5.6 mm), the duodenum(12.6+/-6.4 mm), the kidneys right and left (15.5+/-6.1 mm, 16.2+/-10 mm) and the pancreas (13.2+/-6 mm). No significant variation of volume was observed for these organs. CONCLUSION: The movements of the tumour, the liver and the abdominal organs, induced by breathing are significant. The respiratory gating appears essential in particular with the development of new techniques of irradiation such as the intensity-modulated radiotherapy (IMRT) or the stereotactic body radiation therapy (SBRT).

[Tolerance of the association sucralfate / Cu-Zn salts in radiation dermatitis]. / Tolérance de l'association de sucralfate / sels de Cu-Zn dans les radiodermites.

The aim of this study was to evaluate the tolerance of topical application of the combination sucralfate / copper zinc salts in radiation dermatitis in women suffering from breast cancer and treated by radiotherapy. 47 patients (average age : 57,5 years) that have to be treated by radiation therapy on non lesional areas, were included into this open multicentric study. They had to apply Cicalfate cream twice a day, from the fi rst radiation therapy session and during 10 weeks. Patients were treated by photon- or electrontherapy (72 % et 28 %, respectively; cumulated total dose : 58,6Gy). Tolerance was considered to be excellent. The radiation dermatitis (score NCIC > or = 2) was noted at the 3rd week of radiotherapy only in 5 % of the subjects and in 53 % of the subjects, the last week of treatment. Pruritus was significantly increased at D21. Pain and discomfort were increased at D28, but remained low intensity. The soothing effect of the combination of sucralfate/ copper zinc salts were considered satisfying or very satisfying by investigators and patients during the study, varying from 94 to 100 % of satisfaction. The impact of radiation therapy on the patients'quality of life, assessed by DLQI, evaluated at the end of the study was not statistically different from the score calculated at D7 (DLQI=0,8 et D7 versus DLQI=1 at D70). Thus, topical application of the combination sucralfate / copper zinc salts can be used in the indication radiation dermatitis.

Phase III randomized trial of Calendula officinalis compared with trolamine for the prevention of acute dermatitis during irradiation for breast cancer.

PURPOSE: The effectiveness of nonsteroid topical agents for the prevention of acute dermatitis during adjuvant radiotherapy for breast carcinoma has not been demonstrated. The goal of this study was to compare the effectiveness of calendula (Pommade au Calendula par Digestion; Boiron Ltd, Levallois-Perret, France) with that of trolamine (Biafine; Genmedix Ltd, France), which is considered in many institutions to be the reference topical agent. PATIENTS AND METHODS: Between July 1999 and June 2001, 254 patients who had been operated on for breast cancer and who were to receive postoperative radiation therapy were randomly allocated to application of either trolamine (128 patients) or calendula (126 patients) on the irradiated fields after each session. The primary end point was the occurrence of acute dermatitis of grade 2 or higher. Prognostic factors, including treatment modalities and patient characteristics, were also investigated. Secondary end points were the occurrence of pain, the quantity of topical agent used, and patient satisfaction. RESULTS: The occurrence of acute dermatitis of grade 2 or higher was significantly lower (41% v 63%; P <.001) with the use of calendula than with trolamine. Moreover, patients receiving calendula had less frequent interruption of radiotherapy and significantly reduced radiation-induced pain. Calendula was considered to be more difficult to apply, but self-assessed satisfaction was greater. Body mass index and adjuvant chemotherapy before radiotherapy after lumpectomy were significant prognostic factors for acute dermatitis. CONCLUSION: Calendula is highly effective for the prevention of acute dermatitis of grade 2 or higher and should be proposed for patients undergoing postoperative irradiation for breast cancer.

[Evolution of the use of the portal imaging device: prospective study over three years]. / Evolution des concepts d'utilisation de l'imagerie électronique: étude prospective sur trois périodes.

PURPOSE: To describe the evolution of the use of the electronic portal imaging device (EPID) over three periods. MATERIAL AND METHODS: From 1990, as part of the quality assurance research programs, the radiotherapy department of the G.-F. Leclerc Centre of Dijon used EPID systems in a prospective fashion. During the first of the three periods (PER 1:1990-1993), the study consisted of analysis criteria determination, software efficiency improvement and a selection of patients who could benefit from the method. Eight hundred and forty-five images of 40 patients were analysed qualitatively and quantitatively. Two verifications per week were planned, and the action level for correction was 10 mm. Head and neck images were also displayed in 'cinema' presentation for internal movements analysis. From 1994 to 1995 (PER 2), off-line procedure (OLP) based upon early correction of the systematic error and the rules calculated from our previous experience were tested for checking the brain, head and neck (LOC 1: 396 images) and many of the pelvic irradiations (LOC 2: 260 images). A double-exposure procedure and/or movie loop presentation was reserved for other patients. During the last period (PER 3: 1996-1997), the OLP procedure was routinely performed in 54 patients (images: 321 LOC 1, 680 LOC 2). RESULTS: LOC 1: deviations of < 3 mm increased from 75.5% during PER 1 to 81% during PER 2 to 83% during PER3. Conversely, deviations of 3-5 mm dropped from 19.5 to 13%, while deviations of more than 5 mm remained stable, around 5%. The actual standard error of the mean deviation observed was 2 mm. LOC 2: deviations of < 5 mm were observed in 81% of the cases during PER 1 and in 91% during PER 3 (89.5% in PER 2). These good results led to a decrease in deviation of 5 to 7 mm (11 to 6%) and also to a significant drop in deviations of more than 7 mm, 8 to 3% respectively. The actual precision obtained was 2.5 mm +/- 3 mm SD. CONCLUSIONS: The OLP based upon the early correction of the systematic error led to a significant increase of setup accuracy of patients irradiated for the brain, head and neck, and especially for pelvic lesions.

High dose rate brachytherapy for superficial cancer of the esophagus.

PURPOSE: We analyzed our experience with external radiotherapy, combined modality treatment, or HDR brachytherapy alone to limited esophageal cancers. METHODS AND MATERIALS: From 1991 to 1996, 25 patients with limited superficial esophagus carcinomas were treated by high dose rate brachytherapy. The mean age was 63 years (43-86 years). Five patients showed superficial local recurrence after external radiotherapy. Eleven patients without invasion of the basal membrane were staged as Tis. Fourteen patients with tumors involving the submucosa without spreading to the muscle were staged as T1. Treatment consisted of HDR brachytherapy alone in 13 patients, external radiotherapy and brachytherapy in 8 cases, and concomitant chemo- and radiotherapy in 4 cases. External beam radiation was administered to a total dose of 50 Gy using 2 Gy daily fractions in 5 weeks. In cases of HDR brachytherapy alone (13 patients), 6 applications were performed once a week. RESULTS: The mean follow-up is 31 months (range 24-96 months). Twelve patients received 2 applications and 13 patients received 6 applications. Twelve patients experienced a failure (48%), 11/12 located in the esophagus, all of them in the treated volume. One patient presented an isolated distant metastasis. In the patients treated for superficial recurrence, 4/5 were locally controlled (80%) by brachytherapy alone. After brachytherapy alone, 8/13 patients were controlled (61%). The mean disease-free survival is 14 months (1-36 months). Overall survival is 76% at 1 year, 37% at 2 years, and 14% at 3 years. Overall survival for Tis patients is 24% vs. 20% for T1 (p = 0.83). Overall survival for patients treated by HDR brachytherapy alone is 43%. One patient presented with a fistula with local failure after external radiotherapy and brachytherapy. Four stenosis were registered, two were diagnosed on barium swallowing without symptoms, and two required dilatations. CONCLUSION: High dose rate brachytherapy permits the treating of patients with superficial esophageal cancer with good tolerance. Early tumors, located in the mucosa, might be treated by HDR brachytherapy alone or by a combined modality treatment in which HDR brachytherapy can take place like a boost. This approach may cure localized recurrences.

Preoperative radiotherapy and surgery for endometrial carcinoma: prognostic significance of the sterilization of the specimen.

INTRODUCTION: We report a retrospective study on the analysis of the operative specimen after preoperative radiotherapy for FIGO (1971) stage I or II endometrial carcinoma. METHODS AND MATERIALS: From 1976 to 1996, 221 patients were treated with external radiotherapy (XRT) and/or low-dose-rate brachytherapy (BT) followed by surgery (S). Patients with cervical involvement (89 patients) or with high-grade tumors (49 patients) received XRT and BT. Patients stage FIGO Ia (89 patients) or with low-grade tumors (57 patients) received BT alone. Surgery was performed 5 to 6 weeks after irradiation. RESULTS: The mean follow-up is 78 months (12-216). The 5-year survival was 90% for FIGO Ia, 80% for FIGO Ib, and 84% for FIGO II (p = 0.51). According to the differentiation, 5-year survival was 87% for grade 1, 84% for grade 2, 84% for grade 3 (p = 0.10). Grade 3 complications were registered in 2% (no grade 4). The tumors were sterilized in 37 patients (17%), sterilized but with dystrophic glands in 34 patients (16%), only modified and altered in 21 patients (9.5%), with viable cells in 56 patients (26%). After preoperative radiotherapy, 37/148 specimens were sterilized (25%), 14/74 after brachytherapy and surgery (19%), 23/74 after external radiotherapy-brachytherapy and surgery (31%). According to the response of the specimen, 5-year survival was 87% when the tumor was sterilized, 96% when altered glands were present, 85% when modified, and 76% if residual tumor with viable cells was identified (p = 0.043). CONCLUSION: Preoperative radiotherapy followed by surgery is a safe and effective treatment of FIGO stage I or II endometrial carcinomas. BT with two uterine tubes seems to be of interest in the contribution of the treatment of the uterus to sterilize the specimen. The analysis of this new prognostic factor remains important to select a population with worst prognosis.

Conservative management of rectal adenocarcinoma by radiotherapy.

PURPOSE: The aim of this study was to analyze the experience of Centre GF Leclerc for conservative and curative treatment by radiotherapy of low rectal cancer. PATIENTS AND METHODS: A total of 151 patients received radiotherapy alone for rectal adenocarcinoma with curative intent. They were clinically staged according to size (T1 < 3 cm, and T2 > 3 cm) and depth of infiltration (A=superficial, and B=impaired mobility and T3 fixed). Over the past 6 years, rectal ultrasound (US) has been used systematically, compared with computed tomographic scan and magnetic resonance imaging when needed. Intracavitary contact X ray was given to 129 patients (69%), and brachytherapy in 45 of 151. External radiotherapy was used in 34 cases (22.5%). RESULTS: Complete response was obtained in 93%. Local failures were observed in 50 cases (28%); two occurred in pelvic nodes after intracavitary X rays. Size (tumors > 3 cm) and alteration of mobility significantly influenced the rate of local failure (p=0.009 and 0.007). The addition of external radiotherapy in patients with poor prognostic factors improved the local control rate. A total of 39 patients with recurrence were amenable to salvage surgery. After salvage treatment, the local control rate was 82% with unlimited follow-up. The 5-year actuarial survival rate was 57%, with a specific survival of 66%. There was no difference in local control or survival according to differentiation of the tumors and distance between anal margin and the inferior level of the lesion. Severe late effect (grade 3) was 3.8%. The sphincter preservation was obtained in 104 of 124 cases (84%). The sphincter function was judged to normal in 102 of 104 patients (98%). CONCLUSION: Intracavitary contact X ray is the treatment of choice for clinical Stage T1A rectal tumors. External radiotherapy significantly improved the results of treatment of tumors > 3 cm. Clinical staging and transrectal ultrasound allows a safe selection of indications. Radiotherapy alone may be proposed for selected cases as an alternative to mutilating surgery for small rectal adenocarcinoma.

Organ preservation in cervix cancer.

From 1970 to 1994, 642 patients with carcinomas of intact uterine cervix were treated with radiotherapy alone Univariate and multivariate analysis was carried out of predictive factors for: 1) pelvic control and survival rates; 2) complications using French-Italian Syllabus, combined with an evaluation of the impact of customized treatment planning policy (CTP) on G3-G4. According to Figo substaging 30% of patients were stage I, 42% stage II and 28% stage III/IV. Diameter of cervical disease was 3-5 cm in 38% of cases and > 5 cm in 15%. Nodal involvement from lymphangiogram was 21%. The distribution of sequelae and complications was: G1 23%, G2 18%, G3 6%, G4 2.5%. The distribution of G3-G4 per organ was: genitalia 6% (no G4), rectum 4%, colon 1.5%, bladder 1.2%, soft tissues 1%, small bowel 0.5%. Stage (RR ranging from 1.5 for stage IIb to 5 for stage III/IV), tumor size (RR = 1.5), nodal involvement (RR = 2) were significant predictive factors for survival and pelvic control rates (p < 0.0001). In univariate analysis the main factors influencing the risk of G3-G4 complications were: Figo substaging, external radiation dose over 40 Gy (ED), parametrium boost (PB), use of brachytherapy vaginal cylinders applicator (CA), high HWT and mean rectal dose rate for rectal complications. In multivariate analysis, CA remained the only predictive factor for G3-G4 bladder events (odds ratio OR = 10.8) while the increase of mean dose rate (OR = 1.1), use of CA (OR = 4.2) and ED > 40 Gy (OR = 4.4) were predictive of severe rectal sequelae. Prevention of complications based upon individual changes of treatment planning according to dosimetry parameters led to a sharp decrease in severe complications with time. No G4 occurred after 1983. G3 rates dropped from 5% before 1978 to 0% after 1983 in stage I, from 10% to 6% in stage II and from 23% to 12% in stages III/IV. Meanwhile 5-year LC rates remained stable in early stages, about 91% in stage I and 85% in stage II, conversely they fell from 75% to 55% in stages III/IV, thus raising the problem of underdosage and/or more reliable staging with time. It is concluded that radiotherapy prescriptions based upon tumor diameter per stage and delivered using CTP led to an eradication of lethal complications and provided significant decrease of G3 in all cases while maintaining high cure rates in early stages. Dose reduction should be considered with caution in stages III/IV.

[Demyelinating involvement in Borrelian neuropathies]. / Les atteintes démyélinisantes au cours des neuropathies borréliennes.

Five patients (4 men, 1 woman, aged 51-67), were hospitalized for peripheral painful neuropathies. The serological survey and the dramatic responses to penicillin confirmed the responsibility of Borrelia burgdorferi in all 5 cases. Electromyographical studies showed evidence of demyelination: prolonged distal latency, slowing down of nerve conduction velocity. In 3 patients this pattern was related to axonal degeneration as shown by fibrillation potentials and reduced voluntary motor unit potentials recorded on needle examination. The other two showed no axonal degeneration. One also had motor conduction blocks. Such a demyelination could be due to vasculitis of the vasa nervorum described in tick-bone meningoradiculitis.