L. Claude

Ewing Sarcoma: Current Management and Future Approaches Through Collaboration

Ewing sarcoma (ES) is an aggressive sarcoma of bone and soft tissue occurring at any age with a peak incidence in adolescents and young adults. The treatment of ES relies on a multidisciplinary approach, coupling risk-adapted intensive neoadjuvant and adjuvant chemotherapies with surgery and/or radiotherapy for control of the primary site and possible metastatic disease. The optimization of ES multimodality therapeutic strategies has resulted from the efforts of several national and international groups in Europe and North America and from cooperation between pediatric and medical oncologists. Successive first-line trials addressed the efficacy of various cyclic combinations of drugs incorporating doxorubicin, vincristine, cyclophosphamide, ifosfamide, etoposide, and dactinomycin and identified prognostic factors now used to tailor therapies. The role of high-dose chemotherapy is still debated. Current 5-year overall survival for patients with localized disease is 65% to 75%. Patients with metastases have a 5-year overall survival < 30%, except for those with isolated pulmonary metastasis (approximately 50%). Patients with recurrence have a dismal prognosis. The many insights into the biology of the EWS-FLI1 protein in the initiation and progression of ES remain to be translated into novel therapeutic strategies. Current options and future approaches will be discussed.

Early Variations of Circulating Interleukin-6 and Interleukin-10 Levels During Thoracic Radiotherapy Are Predictive for Radiation Pneumonitis

PURPOSE To investigate variations of circulating serum levels of interleukin-6 (IL-6), tumor necrosis factor alpha (TNFalpha), and interleukin-10 (IL-10) during three-dimensional conformal radiation therapy (3D-CRT) in patients with non-small-cell lung cancer and correlate these variations with the occurrence of radiation pneumonitis. PATIENTS AND METHODS Ninety-six patients receiving 3D-CRT for stage I to III disease were evaluated prospectively. Circulating cytokine levels were determined before, every 2 weeks during, and at the end of treatment. Radiation pneumonitis was evaluated prospectively between 6 and 8 weeks after 3D-CRT. The predictive value of clinical, dosimetric, and biologic (cytokine levels) factors was evaluated both in univariate and multivariate analyses. RESULTS Forty patients (44%) experienced score 1 or more radiation pneumonitis. No association was found between baseline cytokine levels and the risk of radiation pneumonitis. In the whole population, mean levels of TNFalpha, IL-6, and IL-10 remained stable during radiotherapy. IL-6 levels were significantly higher (P = .047) during 3D-CRT in patients with radiation pneumonitis. In the multivariate analysis, covariations of IL-6 and IL-10 levels during the first 2 weeks of 3D-CRT were evidenced as independently predictive of radiation pneumonitis in this series (P = .011). CONCLUSION Early variations of circulating IL-6 and IL-10 levels during 3D-CRT are significantly associated with the risk of radiation pneumonitis. Variations of circulating IL-6 and IL-10 levels during 3D-CRT may serve as independent predictive factors for this complication.

Respiratory gating techniques for optimization of lung cancer radiotherapy

Purpose: The primary objective of the STIC 2003 project was to compare the clinical and economic aspects of respiratory-gated conformal radiotherapy (RGRT), an innovative technique proposed to limit the impact of respiratory movements during irradiation, versus conventional conformal radiotherapy, the reference radiation therapy for lung cancer. Methods and Materials: A comparative, nonrandomized, multicenter, and prospective cost toxicity analysis was performed in the context of this project between April 2004 and June 2008 in 20 French centers. Only the results of the clinical study are presented here, as the results of the economic assessment have been published previously. Results: The final results based on 401 evaluable patients confirm the feasibility and good reproducibility of the various RGRT systems. The results of this study demonstrated a marked reduction of dosimetric parameters predictive of pulmonary, cardiac and esophageal toxicity as a result of the various respiratory gating techniques. These dosimetric benefits were mainly observed with deep inspiration breath-hold (DIBH) techniques (ABC and SDX systems), which markedly increased the total lung volume compared with the inspiration-synchronized system based on tidal volume (Real-time Position Management). These theoretical dosimetric benefits were correlated clinically with a significant reduction of pulmonary acute toxicity, and the pulmonary, cardiac, and esophageal late toxicities, especially with DIBH techniques. Pulmonary function parameters, although more heterogeneous, especially DLCO, showed a tendency to reduction of pulmonary toxicity in the RGRT group. Conclusions: RGRT seems to be essential to reduce toxicities, especially the pulmonary, cardiac, and esophageal late toxicities with the DIBH methods.

Predictive Factors of Late Radiation Fibrosis: A Prospective Study in Non-Small Cell Lung Cancer

PURPOSE To determine predictive factors of late radiation fibrosis (RF) after conformal radiotherapy (3D-RT) in non-small cell lung cancer (NSCLC). METHODS AND MATERIALS Ninety-six patients with Stage IA-IIIB NSCLC were included in a prospective trial. Clinical evaluation, chest X-ray, and pulmonary functional tests including diffusion parameters were performed before and 6 months after radiotherapy. An independent panel of experts prospectively analyzed RF, using Late Effects in Normal Tissues-Subjective, Objective, Management and Analytic scales classification. Logistic regression analysis was performed to identify relationships between clinical, functional, or treatment parameters and incidence of RF. Variations of circulating serum levels of pro-inflammatory (interleukin-6, tumor necrosis factor alpha, tumor growth factor beta1) and anti-inflammatory (interleukin-10) cytokines during 3D-RT were examined to identify correlations with RF. RESULTS Of the 96 patients included, 72 were evaluable for RF at 6 months. Thirty-seven (51.4%) developed RF (Grade >or=1), including six severe RF (Grades 2-3; 8.3%). In univariate analysis, only poor Karnofsky Performance Status and previous acute radiation pneumonitis were associated with RF (p < 0.05). Dosimetric factors (mean lung dose, percentage of lung volume receiving more than 10, 20, 30, 40, and 50 Gy) were highly correlated with RF (p < 0.001). In multivariate analysis, previous acute radiation pneumonitis and dosimetric parameters were significantly correlated with RF occurrence. It was not significantly correlated either with cytokines at baseline or with their variation during 3D-RT. CONCLUSIONS This study confirms the importance of dosimetric parameters to limit the risk of RF. Contrary to acute radiation pneumonitis, RF was not correlated to cytokine variations during 3D-RT.

Fertility and Pregnancy Outcome After Abdominal Irradiation That Included or Excluded the Pelvis in Childhood Tumor Survivors

PURPOSE To evaluate fertility after abdominal and/or pelvic irradiation in long-term female survivors. METHODS AND MATERIALS Puberty and pregnancy outcome were analyzed in female survivors of childhood cancer (aged <18 years) treated with abdominal and/or pelvic radiotherapy (RT) at one of two French centers (Nancy and Lyon) between 1975 and 2004. Data were obtained from medical records and questionnaires sent to the women. RESULTS A total of 84 patients who had received abdominal and/or pelvic RT during childhood and were alive and aged more than 18 years at the time of the study made up the study population. Of the 57 female survivors treated with abdominal RT that excluded the pelvis, 52 (91%) progressed normally through puberty and 23 (40%) had at least one recorded pregnancy. Of the 27 patients treated with pelvic RT, only 10 (37%) progressed normally through puberty and 5 (19%) had at least one recorded pregnancy. Twenty-two women (seventeen of whom were treated with pelvic RT) had certain subfertility. A total of 50 births occurred in 28 women, with one baby dying at birth; one miscarriage also occurred. There was a high prevalence of prematurity and low birth weight but not of congenital malformations. CONCLUSIONS Fertility can be preserved in patients who undergo abdominal RT that excludes the pelvis, taking into account the other treatments (e.g., chemotherapy with alkylating agents) are taken into account. When RT includes the pelvis, fertility is frequently impaired and women can have difficulty conceiving. Nevertheless, pregnancies can occur in some of these women. The most important factor that endangers a successful pregnancy after RT is the total dose received by the ovaries and uterus. This radiation dose has to be systematically recorded to improve our ability to follow up patients.

Is abdominal compression useful in lung stereotactic body radiation therapy? A 4DCT and dosimetric lobe-dependent study

PURPOSE To determine the usefulness of abdominal compression in lung stereotactic body radiation therapy (SBRT) depending on lobe tumor location. MATERIALS AND METHODS Twenty-seven non-small cell lung cancer patients were immobilized in the Stereotactic Body Frame™ (Elekta). Eighteen tumors were located in an upper lobe, one in the middle lobe and nine in a lower lobe (one patient had two lesions). All patients underwent two four-dimensional computed tomography (4DCT) scans, with and without abdominal compression. Three-dimensional tumor motion amplitude was determined using manual landmark annotation. We also determined the internal target volume (ITV) and the influence of abdominal compression on lung dose-volume histograms. RESULTS The mean reduction of tumor motion amplitude was 3.5 mm (p = 0.009) for lower lobe tumors and 0.8 mm (p = 0.026) for upper/middle lobe locations. Compression increased tumor motion in 5 cases. Mean ITV reduction was 3.6 cm(3) (p = 0.039) for lower lobe and 0.2 cm(3) (p = 0.048) for upper/middle lobe lesions. Dosimetric gain of the compression for lung sparing was not clinically relevant. CONCLUSIONS The most significant impact of abdominal compression was obtained in patients with lower lobe tumors. However, minor or negative effects of compression were reported for other patients and lung sparing was not substantially improved. At our institute, patients with upper or middle lobe lesions are now systematically treated without compression and the usefulness of compression for lower lobe tumors is evaluated on an individual basis.

Influence of Nucleoshuttling of the ATM Protein in the Healthy Tissues Response to Radiation Therapy: Toward a Molecular Classification of Human Radiosensitivity

PURPOSE Whereas post-radiation therapy overreactions (OR) represent a clinical and societal issue, there is still no consensual radiobiological endpoint to predict clinical radiosensitivity. Since 2003, skin biopsy specimens have been collected from patients treated by radiation therapy against different tumor localizations and showing a wide range of OR. Here, we aimed to establish quantitative links between radiobiological factors and OR severity grades that would be relevant to radioresistant and genetic hyperradiosensitive cases. METHODS AND MATERIALS Immunofluorescence experiments were performed on a collection of skin fibroblasts from 12 radioresistant, 5 hyperradiosensitive, and 100 OR patients irradiated at 2 Gy. The numbers of micronuclei, γH2AX, and pATM foci that reflect different steps of DNA double-strand breaks (DSB) recognition and repair were assessed from 10 minutes to 24 hours after irradiation and plotted against the severity grades established by the Common Terminology Criteria for Adverse Events and the Radiation Therapy Oncology Group. RESULTS OR patients did not necessarily show a gross DSB repair defect but a systematic delay in the nucleoshuttling of the ATM protein required for complete DSB recognition. Among the radiobiological factors, the maximal number of pATM foci provided the best discrimination among OR patients and a significant correlation with each OR severity grade, independently of tumor localization and of the early or late nature of reactions. CONCLUSIONS Our results are consistent with a general classification of human radiosensitivity based on 3 groups: radioresistance (group I); moderate radiosensitivity caused by delay of nucleoshuttling of ATM, which includes OR patients (group II); and hyperradiosensitivity caused by a gross DSB repair defect, which includes fatal cases (group III).

Computed tomographic atlas for the new international lymph node map for lung cancer: A radiation oncologist perspective

PURPOSE To develop a reproducible definition for each mediastinal lymph node station based on the new TNM classification for lung cancer. METHODS AND MATERIALS This paper proposes an atlas using the new international lymph node map used in the seventh edition of the TNM classification for lung cancer. Four radiation oncologists and 1 diagnostic radiologist were involved in the project to put forward a reproducible radiologic description for the lung lymph node stations. RESULTS The International Association for the Study of Lung Cancer lymph node definitions for stations 1 to 11 have been described and illustrated on axial computed tomographic scan images using a certified radiotherapy planning system. CONCLUSIONS This atlas will assist both diagnostic radiologists and radiation oncologists in accurately defining the lymph node stations on computed tomographic scan in patients diagnosed with lung cancer.

A phase 2 trial of whole-brain radiotherapy combined with intravenous chemotherapy in patients with brain metastases from breast cancer

A study was conducted to determine the efficacy, tolerability, and safety of concurrent cisplatin and vinorelbine chemotherapy and radiotherapy in patients with previously untreated brain metastases from breast cancer.

Facteurs prédictifs de la pneumopathie radique aiguë

Thoracic irradiation is a major weapon in the treatment of nonmetastatic primary lung cancer, in particular in patients presenting a locally advanced disease of the mediastinium. Acute radiation pneumonitis (ARP) is one of the main limiting toxicities. The purpose of this work is to sum up the current state of knowledge of the factors of risk of developing ARP. The incidence after conventional irradiation, in patients with non small cell lung cancer (NSCLC) is about 7 to 10% in the moderate although symptomatic forms of ARP and about 1 to 3% in the severe forms. The factors related to the patient, the tumour or treatments prior to the irradiation do not determine any specific risk of ARP besides an age of over 65 years that remains debatable. The validated predictive factors of ARP are mainly related to the irradiation factors (healthy lung volumes irradiated, average dose of irradiation, etc.). Nevertheless, in spite of the adjustment of these parameters, the individual susceptibility to the toxicity of thoracic radiotherapy remains significant, directing current research to the biological markers intrinsic to the patient. In particular, the involvement of early variations of certain cytokines (IL-6, IL-10, TGF-ss) in the occurrence of ARP during irradiation has been suggested and studies are under way to confirm their involvement and determine their role.