L. Thomas

Impact of 3D image-based PDR brachytherapy on outcome of patients treated for cervix carcinoma in France: results of the French STIC prospective study.

PURPOSE In 2005 a French multicentric non randomized prospective study was initiated to compare two groups of patients treated for cervix carcinoma according to brachytherapy (BT) method: 2D vs 3D dosimetry. The BT dosimetric planning method was chosen for each patient in each center according to the availability of the technique. This study describes the results for 705 out of 801 patients available for analysis. PATIENTS AND METHODS For the 2D arm, dosimetry was planned on orthogonal X-Rays using low dose rate (LDR) or pulsed dose rate (PDR) BT. For the 3D arm, dosimetry was planned on 3D imaging (mainly CT) and performed with PDR BT. Each center could follow the dosimetric method they were used to, according to the chosen radioelement and applicator. Manual or graphical optimization was allowed. PATIENTS AND METHODS Three treatment regimens were defined: Group 1: BT followed by surgery; 165 patients (2D arm: 76; 3D arm: 89); Group 2: EBRT (+chemotherapy), BT, then surgery; 305 patients (2D arm: 142; 3D arm: 163); Group 3: EBRT (+chemotherapy), then BT; 235 patients, (2D arm: 118; 3D arm: 117). PATIENTS AND METHODS The DVH parameters for CTVs (High Risk CTV and Intermediate Risk CTV) and organs at risk (OARs) were computed as recommended by GYN GEC ESTRO guidelines. Total doses were converted to equivalent doses in 2Gy fractions (EQD2). Side effects were prospectively assessed using the CTCAEv3.0. RESULTS The 2D and 3D arms were well balanced with regard to age, FIGO stage, histology, EBRT dose and chemotherapy. For each treatment regimen, BT doses and volumes were comparable between the 2D and 3D arms in terms of dose to point A, isodose 60 Gy volume, dose to ICRU rectal points, and TRAK. RESULTS Dosimetric data in the 3D arm showed that the dose delivered to 90% of the High Risk CTV (HR CTV D90) was respectively, 81.2Gy(α/β10), 63.2Gy(α/β10) and 73.1Gy(α/β10) for groups 1, 2 and 3. The Intermediate Risk (IR) CTV D90 was respectively, 58.5Gy(α/β10), 57.3Gy(α/β10) and 61.7Gy(α/β10) for groups 1, 2 and 3. For the OARs, doses delivered to D2cc ranged 60-70Gy(α/β3) for the bladder, 33-61Gy(α/β3) for the rectum, and 44-58Gy(α/β3) for the sigmoid according to the regimen. RESULTS At 24 months, local relapse-free survival was 91.9% and 100% in group 1, 84.7% and 93% in group 2, 73.9% and 78.5% in group 3; grade 3-4 toxicity rate was 14.6% and 8.9% in group 1, 12.5% and 8.8% in group 2, and 22.7% and 2.6% in group 3 for 2D and 3D arm. CONCLUSION This multicentric study has shown that 3D BT is feasible and safe in routine practice. It has improved local control with half the toxicity observed with 2D dosimetry. The combined treatment with radiotherapy and surgery was more toxic than definitive radiotherapy. For patients with advanced tumors, it is necessary to improve coverage of target volumes without raising toxicity.

Surgical resection and radiotherapy for primary retroperitoneal soft tissue sarcoma

METHODS AND MATERIALS Forty-five patients were consecutively treated for primary retroperitoneal soft tissue sarcoma with surgery in combination with radiation therapy in the same institution. The median follow-up time was 53 months (7-108). RESULTS Seventeen (38%) patients had clear microscopic margins (R0 resection), 26 patients (58%) had gross complete surgical excision (R1 resection) and two patients (4%) had a macroscopic residual disease (R2 resection). External radiotherapy doses ranged from 40.8 to 59.4 Gy (mean and median: 49 Gy). Seventeen patients underwent intraoperative radiation therapy (IORT). Moreover, 11 patients received chemotherapy. The overall 1-, 2-, and 5-year survival for all 45 patients were 93, 85 and 60%, respectively. The 1-, 2-, and 5-year locoregional relapse-free rate for the whole group was 91, 70 and 40%, respectively. In univariate analysis, quality of surgery was the only variable to show a significant effect for overall survival (P=0.0386) and for local control (P=0.0059). Tumor size and tumor grade had no statistically significant effect. For the patients receiving IORT+external beam radiation therapy, no difference was observed for survival or locoregional control. The most frequent acute side effects treatment complications were radiation-induced nausea or vomiting (42%) and moderate enteritis (30%). Significant late morbidity was observed for two patients. CONCLUSIONS This study confirms the feasibility of external postoperative radiotherapy with an acceptable level of toxicity. However, the high rate of local relapses (especially in field of radiation) does not demonstrate the usefulness of radiotherapy at the level of dose used and further preferably randomized studies should be planned.

Pulsed dose rate brachytherapy in head and neck cancers. Feasibility study of a French cooperative group

PURPOSE To prospectively evaluate the feasibility of pulsed dose rate (PDR) brachytherapy to mimic the continuous low dose rate (cLDR) iridium wire technique in head and neck carcinomas. MATERIALS AND METHODS A series of 30 patients were included from June 1995 to May 1998. The primaries were located in the oral cavity (four T1, seven T2 and two T3), the velotonsillar arch (eight T1 and eight T2) and the posterior wall (one T3). Thirteen were irradiated by exclusive brachytherapy (dose, > or =45 Gy). The PDR delivered 0.5 Gy/pulse, one pulse/h, day and night, to mimic cLDR irradiation. RESULTS The implantation was feasible for all the patients, usually easy and of good quality. The mean duration/pulse was 13 min, with a mean source activity of 171 mCi. Patient tolerance was poor in nine cases. Sixteen patients could receive the whole PDR treatment with a total ranging from 30 to 120 pulses without any problem. Seven had short breakdowns (< or =6 h). Seven had definitive breakdowns, but could end the irradiation by manual afterloading of iridium 192 wires. The radioprotection was better (or complete), except for one patient. Most of the breakdowns were related to kinking or flattering of the tube. CONCLUSIONS PDR is feasible in head and neck carcinomas, but necessitates improvement of the quality and control of the plastic tubes.

MAGNETIC RESONANCE IMAGING IN THE TREATMENT PLANNING OF RADIATION THERAPY IN CARCINOMA OF THE CERVIX TREATED WITH THE FOUR-FIELD PELVIC TECHNIQUE

PURPOSE To evaluate magnetic resonance imaging (MRI) in the planning of radiation therapy for patients with carcinoma of the cervix treated with a four-field technique. METHODS AND MATERIALS Between May 1994 and February 1995, 18 patients with carcinoma of the cervix were entered in the study (1 T1 N-; 2 T2a N-; 1 T2b NO; 10 T2b N-; 2 T2b N+; 2 T3b N+). Node status was assessed by a laparoscopic pelvic lymphadenectomy. During the first step, all the patients were simulated with an isocentric four-field pelvic technique. In one group (11 patients) simulation was done based on clinical examination, computed tomography (CT), and standard guidelines. In the second group (seven patients) simulation was based on clinical examination, CT, and with the help of diagnostic MRI, which was available at that time. During the second step, MRI in treatment position with skin markings of the isocenter of the radiation fields was then performed in every patient. During the third step, in each patient, the simulated radiation fields were correlated with the MRI defined target volume by superimposing them on midsagittal and midcoronal MR images. The adequacy of the margins was arbitrarly defined as 1 cm around the MRI defined target volume (tumor of the cervix and its extension, and uterus). RESULTS In the first group (11 patients), MRI in treatment position led to a change in 7 patients: six inadequate margins in the lateral fields and one in the anterior and lateral field. In almost all the cases, the adjustments were of an increase of 10 mm, equally matched between the anterior and posterior borders of the lateral fields. In the second group (seven patients), MRI in treatment position has led to a change in lateral fields in five patients. The mean adjustment was 10 mm: four increases (two anterior border, one posterior border, one anterior and posterior border), and one decrease of the posterior border. In the two groups, modifications of the anterior border of the lateral fields have allowed adequate margins around the uterine fundus and modifications of the posterior border have allowed adequate coverage of the cervical tumor. CONCLUSION When treating carcinoma of the cervix with a four-field radiation technique, standard portals do not exist. The design of lateral fields has to be based on individual morbid anatomy, which is given accurately by diagnostic MRI. Magnetic resonance imaging in treatment position assesses the design of simulated lateral fields.

HIGH-DOSE-RATE BRACHYTHERAPY FOR NON-SMALL-CELL LUNG CARCINOMA: A RETROSPECTIVE STUDY OF 226 PATIENTS

PURPOSE To evaluate the efficacy and toxicity of high-dose-rate (HDR) brachytherapy in patients with inoperable endobronchial carcinoma. METHODS AND MATERIALS We retrospectively reviewed the records (April 1991-May 2004) of patients with non-small-cell carcinoma, with no extrabronchial spread on computed tomography scans, who underwent HDR brachytherapy because of contraindications to surgery and external beam radiation therapy. Kaplan-Meier survival curves were compared by the log-rank test. Prognostic factors were analyzed by multivariate analysis. RESULTS 226 patients (223 men, 3 women, mean age: 62.2 years (range, 40-84)) were included. Of those, 217 (97%) had squamous cell carcinoma (Tis/T1/T2/Tx: 60/153/9/4). Dose was prescribed at 1 cm from the radius (24-35 Gy in 4-6 fractions). Mean follow-up was 30.4 months (range, 9-116). Complete endoscopic response rate was 93.6% at 3 months. One hundred twenty-eight patients (56%) died of intercurrent disease (n = 45), local failure (n = 36), metastasis (n = 10), local failure and metastasis (n = 11), complications (n = 13), and other causes (n = 12). The 2-year and 5-year survival rates were, respectively, 57% and 29% (overall) (median, 28.6 months), 81% and 56% (cancer-specific), and 68% and 50% (local disease-free). Acute toxicity included pneumothorax (1.5%) and mucosal inflammation (10%). Late complications were hemoptysis (6.6% with 5% of fatalities), bronchitis (19.5%), and necrosis (3.5%). In multivariate analysis, a distal tumor location and the use of two catheters were associated with improved local disease-free survival (p = 0.003 and p = 0.007, respectively) and a distal tumor location with improved overall survival (p = 0.0001). CONCLUSIONS This large retrospective study confirms that HDR brachytherapy is an efficient and safe treatment in patients with inoperable endobronchial carcinoma.

Intraoperative interstitial iridium brachytherapy in the management of soft tissue sarcomas: preliminary results of a feasibility Phase II study

Between May 1986 and June 1992, 48 patients with soft tissue sarcomas underwent 50 intraoperative interstitial implants in conjunction with conservative tumoral resections. Brachytherapy was part of the initial treatment in 27 cases and was done in 21 other previously treated patients. For the last ones brachytherapy was, in most of the cases, the only treatment in addition to surgery. The implant dose was 40-65 Gy. When combined with external irradiation the mean prescribed dose was 20 Gy (12-25 Gy). With a median follow-up of 33 months, the 3-year actuarial survival rate was 81% and the local disease-free survival 91.7%. Five local failures were observed only in patients with recurrent sarcomas: two were inside the treated volume and three outside (local failure 5/48 = 10.4%). Acute side-effects occurred in 11 patients (11/48 = 23%), with skin breakdown (two cases) infection and hematoma (one case), infection, lymphocele, secondary skin breakdown and vascular rupture (one case), infection and limited skin breakdown (two cases) and delayed healing (five cases). As a consequence, six patients required reoperation but no amputation was necessary. The functional results were good. Only three patients had a moderate limitation of movement. Late complications occurred in five patients: bone fracture (one case), leg oedemas not interfering with normal activity (three cases), peripheral neuropathy fibrosis related requiring surgery (one case). Therefore, this preliminary report shows that adjuvant intraoperative brachytherapy is feasible and is safe in treating soft tissue sarcomas, even in previously irradiated patients. However, further evaluation is needed to determine the real place of intraoperative implant in the management of soft tissue sarcomas.

Prognostic factors in early-stage leiomyosarcoma of the uterus.

Uterine leiomyosarcomas (LMSs) are rare cancers representing less than 1% of all uterine malignancies. Clinical International Federation of Gynecology and Obstetrics (FIGO) stage is the most important prognostic factor. Other significant prognostic factors, especially for early stages, are difficult to establish because most of the published studies have included localized and extra-pelvian sarcomas. The aim of our study was to search for significant prognostic factors in clinical stage I and II uterine LMS. The pathologic features of 108 uterine LMS including 72 stage I and II lesions were reviewed using standardized criteria. The prognostic significance of different pathologic features was assessed. The median follow-up in the whole group was 64 months (range, 6-223 months). The 5-year overall survival (OS) and metastasis-free interval and local relapse-free interval rates in the whole group and early-stage group (FIGO stages I and II) were 40% and 57%, 42% and 50%, 56% and 62%, respectively. Clinical FIGO stage was the most important prognostic factor for OS in the whole group (P = 4 × 10−15). In the stage I and II group, macroscopic circumscription was the most significant factor predicting OS (P = 0.001). In the same group, mitotic score and vascular invasion were associated with metastasis-free interval (P = 0.03 and P = 0.04, respectively). Uterine LMSs diagnosed using standardized criteria have a poor prognosis, and clinical FIGO stage is an ominous prognostic factor. In early-stage LMS, pathologic features such as mitotic score, vascular invasion, and tumor circumscription significantly impact patient outcome.

Impact of dosimetric and clinical parameters on clinical side effects in cervix cancer patients treated with 3D pulse-dose-rate intracavitary brachytherapy

BACKGROUND AND PURPOSE To assess the association between dosimetric/clinical parameters and gastrointestinal/urinary grade 2-4 side effects in cervix cancer patients treated with 3D pulse dose rate brachytherapy. MATERIALS AND METHODS Three hundred and fifty-two patients received brachytherapy associated with external-beam radiotherapy (EBRT) for 266 of them; 236 patients underwent surgery. The doses for the most exposed 2, and 0.1 cm(3) (D(2cc) and D(0.1cc)) volumes of the rectum and bladder as well as bladder ICRU point dose (D(ICRU)) were converted into isoeffective doses in 2-Gy fractions. The clinical parameters analyzed were: age, smoking habits, arteritis, diabetes, previous pelvic surgery, FIGO stage, nodal status, pathology, pelvic surgery, EBRT and chemotherapy. Side effects were prospectively assessed using the CTCAEv3.0. Cutoff dose levels were defined separately for patients treated with EBRT and brachytherapy (Group 1) and with preoperative brachytherapy (Group 2). RESULTS The median follow-up was 23.4months. In Group 1 a significant predictive value of rectum D(0.1cc) and D(2cc), bladder D(0.1cc) and D(ICRU) for gastrointestinal and urinary toxicity was found using as cutoff 83, 68, 109 and 68Gy(α)(/)(β)(3). In Group 2 a significant predictive value of bladder D(0.1cc), D(2cc) and D(ICRU) for urinary toxicity was found using as cutoff 141, 91 and 67Gy(α)(/)(β)(3), but not for the rectum D(0.1cc) and D(2cc); smoking had a significant predictive value on urinary toxicity. CONCLUSIONS For patients treated with brachytherapy and EBRT, rectum D(0.1cc) and D(2cc) and bladder D(0.1cc) and D(ICRU) had a predictive value for toxicity. For patients treated with preoperative brachytherapy, bladder D(0.1cc), D(2cc) and D(ICRU) and smoking had a predictive value for urinary toxicity.

PIK3CA Pathway Mutations Predictive of Poor Response Following Standard Radiochemotherapy ± Cetuximab in Cervical Cancer Patients

Purpose: EGFR is frequently overexpressed in cervical cancer, suggesting EGFR blockade as a promising treatment approach. Cetuximab, an anti EGFR antibody, used conjointly with radiochemotherapy, was feasible in first-line treatment of cervix carcinoma limited to the pelvis. Experimental Design: This randomized phase II trial enrolled 78 FIGO stage IB2–IIIB cervical cancer patients to either cisplatin-based radiochemotherapy alone (arm B, n = 38) or conjointly with a 6-week course of weekly cetuximab (arm A, n = 40). Brachytherapy was given to the pelvic mass. Primary endpoint was disease-free survival (DFS) at 2 years. EGFR expression and targeted sequencing were performed in 54 of 78 patients. Results: Cetuximab over a 6-week period did not improve DFS at 24 months. At 31 months median follow-up, DFS was not significantly different (P = 0.18). Complete response at 4 to 6 months was strongly predictive for excellent DFS (log-rank test; P < 0.001). PIK3CA, KRAS, and STK11 mutations were observed in 22%, 4%, and 2% of patients, respectively. No tumor with a PI3K pathway mutation showed complete response (0/8 in arm A and 0/6 in arm B), whereas 14 of 52 (27%) tumors without mutations did (P = 0.021). PI3K pathway-mutated tumors showed a trend toward poorer DFS (P = 0.06) following cetuximab (8/22) as compared with those following standard treatment only (6/18). Conclusions: Similar to patients with head and neck cancer, patients with cervical cancer showed no gain in DFS at 2 years following a combined treatment of cetuximab with radiochemotherapy. Although treatment tolerance and compliance were satisfactory, it remains to be demonstrated whether maintenance therapy with cetuximab could be beneficial in selected patient groups. Clin Cancer Res; 21(11); 2530–7. ©2015 AACR.

Curiethérapie intégrant l’imagerie dans la prise en charge des patientes atteintes d’un cancer du col utérin

Deep modifications have occurred these last years in the brachytherapy use in patients with cervix cancer. Imaging allowed a more precise definition of the volumes of interest linked to the tumour and its extension as well as a better visualization of organs at risk. Recommendations on delineation modalities were published in 2005, leading to definition homogeneity, even if large variations are still observed among centres, in terms of techniques and doses. These new definitions also served as basis for new applicators development, allowing a combination of interstitial and endocavitary techniques. Results from centres using image-guided brachytherapy (MRI in particular) evidenced local control improvement, without increase in complications. Retrospective and prospective studies are currently under evaluation. These studies will likely be able to determine dose required to sterilize tumours, as a function of stage and size, as well as dose limits for organs at risk.