Dimitri Lefkopoulos

Role of Cancer Treatment in Long-Term Overall and Cardiovascular Mortality After Childhood Cancer

PURPOSE The purpose of this study was to assess the role of treatment in long-term overall and cardiovascular mortality after childhood cancer. PATIENTS AND METHODS We studied 4,122 5-year survivors of a childhood cancer diagnosed before 1986 in France and the United Kingdom. Information on chemotherapy was collected, and the radiation dose delivered to the heart was estimated for 2,870 patients who had received radiotherapy. RESULTS After 86,453 person-years of follow-up (average, 27 years), 603 deaths had occurred. The overall standardized mortality ratio (SMR) was 8.3-fold higher (95% CI, 7.6-fold to 9.0-fold higher) in relation to the general populations in France and the United Kingdom. Thirty-two patients had died as a result of cardiovascular diseases (ie, 5.0-fold [95% CI, 3.3-fold to 6.7-fold] more than expected). The risk of dying as a result of cardiac diseases (n = 21) was significantly higher in individuals who had received a cumulative anthracycline dose greater than 360 mg/m(2) (relative risk [RR], 4.4; 95% CI, 1.3 to 15.3) and in individuals who received an average radiation dose that exceeded 5 Gy (RR, 12.5 and 25.1 for 5 to 14.9 Gy and > 15 Gy, respectively) to the heart. A linear relationship was found between the average dose of radiation to the heart and the risk of cardiac mortality (estimated excess [corrected] RR at 1 Gy, 60%). CONCLUSION This study is the first, to our knowledge, to establish a relationship between the radiation dose received by the heart during radiotherapy for a childhood cancer and long-term cardiac mortality. This study also confirms a significant excess risk of cardiac mortality associated with a high cumulative dose of anthracyclines.

Epidermoid carcinoma of the anal canal. Results of curative-intent radiation therapy in a series of 270 patients.

Background. Epidermoid carcinoma of the anal canal is an uncommon disease, and most institutions have only a small series of patients. The current study of a large series of patients treated with radiation therapy in a single institution evaluates the outcome, prognostic factors, and the late complications for these patients.

Frequency Distribution of Second Solid Cancer Locations in Relation to the Irradiated Volume Among 115 Patients Treated for Childhood Cancer

PURPOSE To provide better estimates of the frequency distribution of second malignant neoplasm (SMN) sites in relation to previous irradiated volumes, and better estimates of the doses delivered to these sites during radiotherapy (RT) of the first malignant neoplasm (FMN). METHODS AND MATERIALS The study focused on 115 patients who developed a solid SMN among a cohort of 4581 individuals. The homemade software package Dos_EG was used to estimate the radiation doses delivered to SMN sites during RT of the FMN. Three-dimensional geometry was used to evaluate the distances between the irradiated volume, for RT delivered to each FMN, and the site of the subsequent SMN. RESULTS The spatial distribution of SMN relative to the irradiated volumes in our cohort was as follows: 12% in the central area of the irradiated volume, which corresponds to the planning target volume (PTV), 66% in the beam-bordering region (i.e., the area surrounding the PTV), and 22% in regions located more than 5 cm from the irradiated volume. At the SMN site, all dose levels ranging from almost zero to >75 Gy were represented. A peak SMN frequency of approximately 31% was identified in volumes that received <2.5 Gy. CONCLUSION A greater volume of tissues receives low or intermediate doses in regions bordering the irradiated volume with modern multiple-beam RT arrangements. These results should be considered for risk-benefit evaluations of RT.

Impact of treatment time and dose escalation on local control in locally advanced cervical cancer treated by chemoradiation and image-guided pulsed-dose rate adaptive brachytherapy.

PURPOSE To report the prognostic factors for local control in patients treated for locally advanced cervical cancer with image guided pulsed-dose rate brachytherapy. MATERIALS/METHODS Patients treated with curative intent by a combination of external beam radiotherapy and pulsed-dose rate brachytherapy were selected. Local failure was defined as any relapse in the cervix, vagina, parametria, or uterus during follow-up. Prognostic factors were selected based on log rank tests and then analyzed with a Cox model. Dose/effect correlations were performed using the probit model. RESULTS Two hundred and twenty-five patients treated from 2006 to 2011 were included. According to the FIGO classification, 29% were stage IB, 58% stage II, 10% stage III, and 3% stage IVA; 95% received concomitant chemotherapy. Thirty patients were considered having incomplete response or local failure. Among the selected parameters, D90 for HR-CTV, D90 for IR-CTV, the overall treatment time, the TRAK, and the HR-CTV volume appeared significantly correlated with local control in univariate analysis. In multivariate analysis, overall treatment time >55days and HR-CTV volume >30cm(3) appeared as independent. The probit analysis showed significant correlations between the D90 for both CTVs, and the probability of achieving local control (p=0.008 and 0.024). The thresholds to reach to warrant a probability of 90% of local control were 85Gy to the D90 of the HR-CTV and 75Gy to 90% of the IR-CTV (in 2Gy equivalent, α/β=10). To warrant the same local control rate, the D90 HR-CTV should be significantly increased in stage III-IV tumors, in case of HR-CTV >30cm(3), excessive treatment time, or tumor width at diagnosis >5cm (97, 92, 105, and 92Gy respectively). CONCLUSIONS Overall treatment time and HR-CTV volume were independent prognostic factors for local control. The D90 for HR and IR CTV were significantly correlated with local control, and D90 HR-CTV should be adapted to clinical criteria.

Involved-node radiotherapy and modern radiation treatment techniques in patients with Hodgkin lymphoma.

PURPOSE To assess the clinical outcome of the involved-node radiotherapy (INRT) concept using modern radiation treatments (intensity-modulated radiotherapy [IMRT] or deep-inspiration breath-hold radiotherapy [DIBH) in patients with localized supradiaphragmatic Hodgkin lymphoma. METHODS AND MATERIALS All but 2 patients had early-stage Hodgkin lymphoma, and they were treated with chemotherapy prior to irradiation. Radiation treatments were delivered using the INRT concept according to European Organization for Research and Treatment of Cancer guidelines. IMRT was performed with the patient free-breathing. For the adapted breath-hold technique, a spirometer dedicated to DIBH radiotherapy was used. Three-dimensional conformal radiotherapy was performed with those patients. RESULTS Fifty patients with Hodgkin lymphoma (48 patients with primary Hodgkin lymphoma, 1 patient with recurrent disease, and 1 patient with refractory disease) entered the study from January 2003 to August 2008. Thirty-two patients were treated with IMRT, and 18 patients were treated with the DIBH technique. The median age was 28 years (range, 17-62 years). Thirty-four (68%) patients had stage I - (I-IIA) IIA disease, and 16 (32%) patients had stage I - (I-IIB) IIB disease. All but 3 patients received three to six cycles of adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD). The median radiation doses to patients treated with IMRT and DIBH were, respectively, 40 Gy (range, 21.6-40 Gy) and 30.6 Gy (range, 19.8-40 Gy). Protection of various organs at risk was satisfactory. Median follow-up was 53.4 months (range, 19.1-93 months). The 5-year progression-free and overall survival rates for the whole population were 92% (95% confidence interval [CI], 80%-97%) and 94% (95% CI, 75%-98%), respectively. Recurrences occurred in 4 patients: 2 patients had in-field relapses, and 2 patients had visceral recurrences. Grade 3 acute lung toxicity (transient pneumonitis) occurred in 1 case. CONCLUSIONS Our results suggest that patients with localized Hodgkin lymphoma can be safely and efficiently treated using the INRT concept and modern radiation treatment techniques such as IMRT and DIBH.

Dosimetric Benefits of Intensity-Modulated Radiotherapy Combined With the Deep-Inspiration Breath-Hold Technique in Patients With Mediastinal Hodgkin's Lymphoma

PURPOSE To assess the additional benefits of using the deep-inspiration breath-hold (DIBH) technique with intensity-modulated radiotherapy (IMRT) in terms of the protection of organs at risk for patients with mediastinal Hodgkins disease. METHODS AND MATERIALS Patients with early-stage Hodgkins lymphoma with mediastinal involvement were entered into the study. Two simulation computed tomography scans were performed for each patient: one using the free-breathing (FB) technique and the other using the DIBH technique with a dedicated spirometer. The clinical target volume, planning target volume (PTV), and organs at risk were determined on both computed tomography scans according to the guidelines of the European Organization for Research and Treatment of Cancer. In both cases, 30 Gy in 15 fractions was prescribed. The dosimetric parameters retrieved for the statistical analysis were PTV coverage, mean heart dose, mean coronary artery dose, mean lung dose, and lung V20. RESULTS There were no significant differences in PTV coverage between the two techniques (FB vs. DIBH). The mean doses delivered to the coronary arteries, heart, and lungs were significantly reduced by 15% to 20% using DIBH compared with FB, and the lung V20 was reduced by almost one third. The dose reduction to organs at risk was greater for masses in the upper part of the mediastinum. IMRT with DIBH was partially implemented in 1 patient. This combination will be extended to other patients in the near future. CONCLUSIONS Radiation exposure of the coronary arteries, heart, and lungs in patients with mediastinal Hodgkins lymphoma was greatly reduced using DIBH with IMRT. The greatest benefit was obtained for tumors in the upper part of the mediastinum. The possibility of a wider use in clinical practice is currently under investigation in our department.

A pre-clinical assessment of an atlas-based automatic segmentation tool for the head and neck

BACKGROUND AND PURPOSE Accurate conformal radiotherapy treatment requires manual delineation of target volumes and organs at risk (OAR) that is both time-consuming and subject to large inter-user variability. One solution is atlas-based automatic segmentation (ABAS) where a priori information is used to delineate various organs of interest. The aim of the present study is to establish the accuracy of one such tool for the head and neck (H&N) using two different evaluation methods. MATERIALS AND METHODS Two radiotherapy centres were provided with an ABAS tool that was used to outline the brainstem, parotids and mandible on several patients. The results were compared to manual delineations for the first centre (EM1) and reviewed/edited for the second centre (EM2), both of which were deemed as equally valid gold standards. The contours were compared in terms of their volume, sensitivity and specificity with the results being interpreted using the Dice similarity coefficient and a receiver operator characteristic (ROC) curve. RESULTS Automatic segmentation took typically approximately 7min for each patient on a standard PC. The results indicated that the atlas contour volume was generally within +/-1SD of each gold standard apart from the parotids for EM1 and brainstem for EM2 that were over- and under-estimated, respectively (within +/-2SD). The similarity of the atlas contours with their respective gold standard was satisfactory with an average Dice coefficient for all OAR of 0.68+/-0.25 for EM1 and 0.82+/-0.13 for EM2. All data had satisfactory sensitivity and specificity resulting in a favourable position in ROC space. CONCLUSIONS These tests have shown that the ABAS tool exhibits satisfactory sensitivity and specificity for the OAR investigated. There is, however, a systematic over-segmentation of the parotids (EM1) and under-segmentation of the brainstem (EM2) that require careful review and editing in the majority of cases. Such issues have been discussed with the software manufacturer and a revised version is due for release.

Risk of a Second Malignant Neoplasm After Cancer in Childhood Treated With Radiotherapy: Correlation With the Integral Dose Restricted to the Irradiated Fields

PURPOSE After successful treatment of cancers in childhood, the occurrence of second malignant neoplasm (SMN) came to the fore. Few studies have considered the relationship between the radiation dose received and the risk of developing an SMN. To take into account the heterogeneity of the dose distribution so as to evaluate the overall risk of an SMN after a childhood cancer, we therefore focused on the integral dose restricted to the irradiated fields. METHODS AND MATERIALS The study was performed in a cohort of 4,401 patients who were 3-year survivors of all types of childhood cancer treated between 1947 and 1986 in France and Great Britain. For each patient, the integral dose was estimated for the volume inside the beam edges. RESULTS We found a significant dose-response relationship between the overall risk of an SMN and the estimated integral dose. The excess relative risk for each incremental unit of the integral dose was only 0.008 in a linear model and 0.017 when a negative exponential term was considered, when adjusted for chemotherapy. The risk of SMN occurrence was 2.6 times higher in the case of irradiation. However among patients who had received radiotherapy, only those who had received the highest integral dose actually had a higher risk. CONCLUSIONS The integral dose in our study cannot be considered as a good predictor of later risks. However other studies with the same study design are obviously needed to evaluate the use of the integral dose as a tool for decision making concerning different radiotherapy techniques.

Radiation therapy and late mortality from second sarcoma, carcinoma, and hematological malignancies after a solid cancer in childhood.

PURPOSE To compare patterns of long-term deaths due to secondary carcinomas, sarcomas, and hematological malignancies occurring after childhood cancer in a cohort of patients followed over a median of 28 years. METHODS AND MATERIALS The study included 4,230 patients treated at eight institutions, who were at least 5-year survivors of a first cancer, representing 105,670 person-years of observation. Complete clinical, chemotherapeutic, and radiotherapeutic data were recorded, and the integral radiation dose was estimated for 2,701 of the 2,948 patients who had received radiotherapy. The integral dose was estimated for the volume inside the beam edges. The causes of death obtained from death certificates were validated. RESULTS In total, 134 events were due to second malignant neoplasm(s) (SMN). We found that the standardized mortality ratio decreased with increasing follow-up for second carcinomas and sarcomas, whereas the absolute excess risk (AER) increased for a second carcinoma but decreased for second sarcomas. There was no clear variation in SMN and AER for hematological malignancies. We found a significant dose-response relationship between the radiation dose received and the mortality rate due to a second sarcoma and carcinoma. The risk of death due to carcinoma and sarcoma as SMN was 5.2-fold and 12.5-fold higher, respectively, in patients who had received a radiation dose exceeding 150 joules. CONCLUSIONS Among patients who had received radiotherapy, only those having received the highest integral radiation dose actually had a higher risk of dying of a second carcinoma or sarcoma.

/sup 18/F-FDG PET images segmentation using morphological watershed: a phantom study

Segmentation of 18F-FDG PET images could be helpful for delineation of tumor volume in radiotherapy and patient follow-up. The most commonly implemented method on clinical workstations is maximum intensity thresholding, which is inappropriate for heterogeneous uptakes. Our aim was to develop and evaluate a more sophisticated segmentation method, based on the morphological watershed. We developed a segmentation method taking into account PET images characteristics. We evaluated it first on phantom images, using an integrated PET/CT unit and taking CT images as reference images. To simulate tumors in a background activity, we used 6 homogeneous spheres of various volumes in a cylindrical phantom and 3 heterogeneous cylinders in an anthropomorphic phantom. The quality of segmentation was evaluated in terms of volume, shape and position. We compared the results with a maximum intensity threshold segmentation method fitting the volume, taken as reference segmentation. A quantitation analysis completed the phantom study. For both phantom acquisitions, the segmentation obtained with the watershed based algorithm gave satisfying results with the index integrating volume, shape and position. Results considering this index were not significantly different from the reference segmentation (p > 0.5). Errors of volume recovery reached 18% for watershed segmentation. The quantitation analysis on phantoms highlighted partial volume effect, with an error of activity concentration measurement on segmented images ranging between 42% and 51%. Performances of the watershed method evaluated in this study were comparable with an optimized segmentation on phantom images. The quantitation recovery of PET regions with this method was similar with to other segmentation methods.