Safety of adjuvant intensity-modulated postoperative radiation therapy in endometrial cancer: Clinical data and dosimetric parameters according to the International Commission on Radiation Units (ICRU) 83 report.

AIM: To report a single-institution experience using postoperative pelvic Intensity Modulation Radiation Therapy (IMRT) using tomotherapy accelerators (TA) in postoperative endometrial cancer (EC) regarding ICRU 83 recommendations. BACKGROUND: IMRT in gynecological malignancies provides excellent dosimetric data, lower rates of adverse events and clinical data similar to historical series. MATERIAL AND METHODS: Seventy-six patients with EC were postoperatively treated with adjuvant IMRT using TA. The IMRT dose was 45 Gy for patients without positive lymph nodes and Type I histology and 50.4 Gy for patients with positive lymph nodes and/or type II histology. RESULTS: With a median follow-up of 29 months, the 12- and 24-month Overall Survival (OS) and Disease-Free Survival (DFS) were 96%, 93%, 87%, and 74%, respectively. Age of less than 60 years was associated with better OS (HR: 8.9; CI: 1.1-68) and DFS (HR: 3.5; CI: 1.2-10.2). Patients with Type II and Type I Grade III histology had a worse OS (HR: 3.3; CI: 1.1-11). Five women (6.6%) presented in-field local vaginal recurrence, 2 (2.6%) presented non-in-field vaginal recurrence, 4 (5.2%) presented pelvic node and distant recurrence and 11 (14.4%) presented only distant metastases. One patient stopped radiation treatment due to Grade III acute diarrhea. No Grade III late toxicity was observed. Planning Target Volume (PTV) coverage showed mean D2, D50, D95, and D98 of 51.64-46.23 Gy, 49.49-44.97 Gy, 48.62-43.96 Gy, and 48.47-43.58 Gy for patients who received 45 and 50.4 Gy, respectively. CONCLUSIONS: IMRT with TA in postoperative EC shows excellent conformity and homogeneity of PTV dose. Without Grade III late toxicity, data from this cohort demonstrated the utility of IMRT.

External beam radiation therapy followed by high-dose-rate brachytherapy for inoperable superficial esophageal carcinoma.

PURPOSE: The aim of this study was to retrospectively evaluate the feasibility, efficacy, and tolerance of external beam radiotherapy followed by high-dose-rate brachytherapy in inoperable patients with superficial esophageal cancer. PATIENTS AND METHODS: From November 1992 to May 1999, 66 patients with superficial esophageal cancer were treated with exclusive radiotherapy. The median age was 60 years (range, 41-85). Fifty-three percent of them were ineligible for surgery owing to synchronous or previously treated head-and-neck cancer. Most of the patients (n = 49) were evaluated with endoscopic ultrasonography (EUS) or computed tomography (CT). The mean doses of external beam radiotherapy and high-dose rate brachytherapy were 57.1 Gy (+/-4.83) and 8.82 Gy (+/-3.98), respectively. The most frequently used regimen was 60 Gy followed by 7 Gy at 5 mm depth in two applications. RESULTS: Among patients evaluated with EUS or CT, the complete response rate was 98%. The 3-, 5-, and 7-year survival rates were 57.9%, 35.6%, and 26.6%, respectively. Median overall survival was 3.8 years. The 5-year relapse-free survival and cause-specific survival were 54.6% and 76.9%. The 5-year overall, relapse-free, and cause-specific survival of the whole population of 66 patients was 33%, 53%, and 77%, respectively. Local failure occurred in 15 of 66 patients; 6 were treated with brachytherapy. Severe late toxicity (mostly esophageal stenosis) rated according to the Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer scale occurred in 6 of 66 patients (9%). CONCLUSION: This well tolerated regimen may be a therapeutic alternative for inoperable patients with superficial esophageal cancer. Only a randomized study could be able to check the potential benefit of brachytherapy after external beam radiation in superficial esophageal cancer.

Outcomes and patterns of failure in solitary plasmacytoma: a multicenter Rare Cancer Network study of 258 patients.

PURPOSE: To assess the outcomes and patterns of failure in solitary plasmacytoma (SP). METHODS AND MATERIALS: The data from 258 patients with bone (n = 206) or extramedullary (n = 52) SP without evidence of multiple myeloma (MM) were collected. A histopathologic diagnosis was obtained for all patients. Most (n = 214) of the patients received radiotherapy (RT) alone; 34 received chemotherapy and RT, and 8 surgery alone. The median radiation dose was 40 Gy. The median follow-up was 56 months (range 7-245). RESULTS: The median time to MM development was 21 months (range 2-135), with a 5-year probability of 45%. The 5-year overall survival, disease-free survival, and local control rate was 74%, 50%, and 86%, respectively. On multivariate analyses, the favorable factors were younger age and tumor size <4 cm for survival; younger age, extramedullary localization, and RT for disease-free survival; and small tumor and RT for local control. Bone localization was the only predictor of MM development. No dose-response relationship was found for doses >30 Gy, even for larger tumors. CONCLUSION: Progression to MM remains the main problem. Patients with extramedullary SP had the best outcomes, especially when treated with moderate-dose RT. Chemotherapy and/or novel therapies should be investigated for bone or bulky extramedullary SP.

Prognostic factors in solitary plasmacytoma of the bone: a multicenter Rare Cancer Network study.

BACKGROUND: Solitary plasmacytoma (SP) of the bone is a rare plasma-cell neoplasm. There are no conclusive data in the literature on the optimal radiation therapy (RT) dose in SP. Therefore, in this large retrospective study, we wanted to assess the outcome, prognostic factors, and the optimal RT dose in patients with SP. METHODS: Data from 206 patients with bone SP without evidence of multiple myeloma (MM) were collected. Histopathological diagnosis was obtained for all patients. The majority (n = 169) of the patients received RT alone; 32 chemotherapy and RT, and 5 surgery. Median follow-up was 54 months (7-245). RESULTS: Five-year overall survival, disease-free survival (DFS), and local control was 70%, 46%, and 88%; respectively. Median time to MM development was 21 months (2-135) with a 5-year probability of 51%. In multivariate analyses, favorable factors were younger age and tumor size < 5 cm for survival; younger age for DFS; anatomic localization (vertebra vs. other) for local control. Older age was the only predictor for MM. There was no dose-response relationship for doses 30 Gy or higher, even for larger tumors. CONCLUSION: Younger patients, especially those with vertebral localization have the best outcome when treated with moderate-dose RT. Progression to MM remains the main problem. Further investigation should focus on adjuvant chemotherapy and/or novel therapeutic agents.

Harmonization of the Volume of Interest Delineation among All Eleven Radiotherapy Centers in the North of France.

BACKGROUND: Inter-observer delineation variation has been detailed for many years in almost every tumor location. Inadequate delineation can impair the chance of cure and/or increase toxicity. The aim of our original work was to prospectively improve the homogeneity of delineation among all of the senior radiation oncologists in the Nord-Pas de Calais region, irrespective of the conditions of practice. METHODS: All 11 centers were involved. The first studied cancer was prostate cancer. Three clinical cases were studied: a low-risk prostate cancer case (case 1), a high-risk prostate cancer case (pelvic nodes, case 2) and a case of post-operative biochemical elevated PSA (case 3). All of the involved physicians delineated characteristically the clinical target volume (CTV) and organs at risk. The volumes were compared using validated indexes: the volume ratio (VR), common and additional volumes (CV and AV), volume overlap (VO) and Dice similarity coefficient (DSC). A second delineation of the same three cases was performed after discussion of the slice results and the choice of shared guidelines to evaluate homogenization. A comparative analysis of the indexes before and after discussion was conducted using the Wilcoxon test for paired samples. A p-value less than 0.05 was considered to indicate statistical significance. RESULTS: The indexes were not improved in case 1, for which the inter-observer agreement was considered good after the first comparison (DSC = 0.83 ± 0.06). In case 2, the second comparison showed homogenization of the CTV delineation with a significant improvement in CV (81.4 ± 11.7 vs. 88.6 ± 10.26, respectively, p = 0.048), VO (0.41 ± 0.09 vs. 0.47 ± 0.07, respectively; p = 0.009) and DSC (0.58 ± 0.09 vs. 0.63 ± 0.07, respectively; p = 0.0098). In case 3, VR and AV were significantly improved: VR: 1.71(± 0.6) vs. 1.34(± 0.46), respectively, p = 0.0034; AV: 46.58(± 14.50) vs. 38.08(± 15.10), respectively, p = 0.0024. DSC was not improved, but it was already superior to 0.6 in the first comparison. CONCLUSION: Our prospective work showed that a collaborative discussion about clinical cases and the choice of shared guidelines within an established framework improved the homogeneity of CTV delineation among the senior radiation oncologists in our region.

Exclusive low-dose-rate brachytherapy in 279 patients with T2N0 mobile tongue carcinoma.

PURPOSE: To evaluate the therapeutic results obtained with (192)Ir low-dose-rate interstitial brachytherapy in T2N0 mobile tongue carcinoma. PATIENTS AND METHODS: Between December 1979 and January 1998, 279 patients with T2N0 mobile tongue carcinoma were treated by exclusive low-dose-rate brachytherapy, with or without neck dissection. (192)Ir brachytherapy was performed according to the "Paris system" with a median total dose of 60 Gy (median dose rate, 0.5 Gy/h). RESULTS: Overall survival was 74.3% and 46.6% at 2 and 5 years. Local control was 79.1% at 2 years and regional control, respectively, 75.9% and 69.5% at 2 and 5 years (Kaplan-Meier method). Systematic dissection revealed 44.6% occult node metastases, and histologic lymph node involvement was identified as the main significant factor for survival. Complication rate was 16.5% (Grade 3, 2.9%). Half of the patients presented previous and/or successive malignant tumor (ear-nose-throat, esophagus, or bronchus). CONCLUSION: Exclusive low-dose-rate brachytherapy is an effective treatment for T2 tongue carcinoma. Regional control and survival are excellent in patients undergoing systematic neck dissection, which is mandatory in our experience because of a high rate of occult lymph node metastases.

Concomitant Chemoradiotherapy With Image-guided Pulsed Dose Rate Brachytherapy as a Definitive Treatment Modality for Early-stage Cervical Cancer.

PURPOSE: Concurrent chemoradiotherapy (CRT) is the standard of care for patients with bulky cervical cancer. This study aimed to determine the feasibility, tolerance, and effectiveness of pulsed dose rate (PDR) image-guided brachytherapy (IGBT), utilizing magnetic resonance imaging (MRI) planning after CRT for stages IB2 and II cervix cancer patients. METHODS AND MATERIALS: This study planned to include patients with histologically confirmed stage IB2 and II cervical cancer who were treated with CRT followed by a PDR IGBT boost from January 2009 to December 2009 in our institution. All patients had at least a partial response after CRT before IGBT. The institutional review board approved the study. Patients received a 45-Gy external beam radiotherapy (EBRT) to the pelvis with concomitant weekly cisplatin (40 mg/m) for 5 cycles. All patients then underwent reimaging using MRI before BT. The IGBT boost was accomplished with one insertion using an MRI-compatible tandem and ovoid applicator delivering 30 to 35 Gy to a high-risk clinical target volume. Treatment-induced adverse events (AEs), dose parameters, local control, progression-free survival, and overall survival are reported. RESULTS: Forty patients were included in this study, with ages ranging from 31 to 65 years (median age, 45 y). Of all the patients, 12.5% and 5% experienced grade 3 to 4 acute gastrointestinal and genitourinary AEs, respectively, and 2.5% and 2.5% had grade 3 to 4 chronic gastrointestinal and genitourinary AEs, respectively. Within a median follow-up of 30 months (range, 7 to 40 mo), local control was 90%, progression-free survival was 87.5%, and overall survival was 100%. CONCLUSIONS: Intracavitary MRI PDR-IGBT boost after CRT is a feasible, tolerable, and effective treatment modality for patients with stages IB2 and II cervical cancer.

Conformal radiotherapy optimization with micromultileaf collimators: comparison with radiosurgery techniques.

PURPOSE: Conformal radiotherapy (CRT) consists of irradiating the target volume while avoiding the healthy peripheral tissues and organs at risk as far as possible. One technique used to treat intracranial tumors consists of using micromultileaf collimators (MMLCs). Given the dose constraints involved, it is of interest to optimize MMLC irradiation parameters and compare the results of this technique with those of conventional radiosurgery (RT) techniques (Gamma Knife and linear accelerator stereotactic RT). METHODS AND MATERIALS: MMLC protocols are optimized in two stages. The orientation of the fields, delimited by a beam's eye view technique, is determined using a genetic algorithm method. The weighting of the fields and subfields when using intensity modulation and the position of the leaves are optimized using a simulated annealing method. We compared the results obtained for 8 clinical cases using 5 intensity-modulated fields with those obtained using the two radiosurgery techniques. The comparison indexes are those defined by the Radiation Therapy Oncology Group (RTOG). RESULTS: The results of this study demonstrated the advantages of using intensity modulation and the improvement obtained for the RTOG indexes in the case of CRT with MMLC, although the healthy peripheral tissues were less exposed to radiation with the radiosurgery techniques. The results also highlight the difficulty encountered with radiosurgery techniques in obtaining satisfactory dose homogeneity when the protocol is defined with numerous iosocenters. CONCLUSION: In CRT with MMLC, intensity modulation makes it possible to reduce the number of fields used. It is especially useful to optimize the orientations in the case of target volumes of complex shape or when volumes at risk are in the vicinity of the target. If used correctly, MMLC can be a valuable alternative to conventional radiosurgery techniques.

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 user's 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.

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/ß10), 63.2Gy(α/ß10) and 73.1Gy(α/ß10) for groups 1, 2 and 3. The Intermediate Risk (IR) CTV D90 was respectively, 58.5Gy(α/ß10), 57.3Gy(α/ß10) and 61.7Gy(α/ß10) for groups 1, 2 and 3. For the OARs, doses delivered to D2cc ranged 60-70Gy(α/ß3) for the bladder, 33-61Gy(α/ß3) for the rectum, and 44-58Gy(α/ß3) 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.

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)(/)(ß)(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)(/)(ß)(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.

Robotic image-guided reirradiation of lateral pelvic recurrences: preliminary results.

BACKGROUND: The first-line treatment of a pelvic recurrence in a previously irradiated area is surgery. Unfortunately, few patients are deemed operable, often due to the location of the recurrence, usually too close to the iliac vessels, or the associated surgical morbidity. The objective of this study is to test the viability of robotic image-guided radiotherapy as an alternative treatment in inoperable cases. METHODS: Sixteen patients previously treated with radiotherapy were reirradiated with CyberKnife® for lateral pelvic lesions. Recurrences of primary rectal cancer (4 patients), anal canal (6), uterine cervix cancer (4), endometrial cancer (1), and bladder carcinoma (1) were treated. The median dose of the previous treatment was 45 Gy (EqD2 range: 20 to 96 Gy). A total dose of 36 Gy in six fractions was delivered with the CyberKnife over three weeks. The responses were evaluated according to RECIST criteria. RESULTS: Median follow-up was 10.6 months (1.9 to 20.5 months). The actuarial local control rate was 51.4% at one year. Median disease-free survival was 8.3 months after CyberKnife treatment. The actuarial one-year survival rate was 46%. Acute tolerance was limited to digestive grade 1 and 2 toxicities. CONCLUSIONS: Robotic stereotactic radiotherapy can offer a short and well-tolerated treatment for lateral pelvic recurrences in previously irradiated areas in patients otherwise not treatable. Efficacy and toxicity need to be evaluated over the long term, but initial results are encouraging.

Therapeutic value of pretherapeutic extraperitoneal laparoscopic staging of locally advanced cervical carcinoma.

BACKGROUND: Although cervical cancer is clinically staged, surgery has long been considered the best means to assess extrapelvic disease and remains the gold standard for the detection of both intraperitoneal spread and small volume nodal metastases. The objective of this study was to determine short- and long-term outcomes for patients with locally advanced cervical cancer who underwent pretherapeutic laparoscopic staging. METHODS: From 1997 to 2004, 184 patients with stages IB2-IVA cervical cancer underwent pretherapeutic laparoscopic staging procedure including transperitoneal abdomino-pelvic exploration and extraperitoneal bilateral infrarenal paraaortic lymph node dissection. Patients were then treated with definitive radiotherapy tailored according to the staging results. RESULTS: The median age and BMI were respectively 45.8 years old and 27.1 kg/m2. Most lesions were squamous (n=172) and clinical stage was evenly distributed. Median operative time was 155 min with an average of 20.8 lymph nodes removed. Postoperative hospital stay averaged 1.4 days. Major complications included 1 intraoperative ureteral injury and 1 postoperative bowel obstruction from an umbilical trocar site hernia. The final pathology revealed that 44 patients (24.3%) had metastatic disease within paraaortic lymph nodes. With a median follow-up of 26.8 months (average 32.9), 67 patients (36.4%) had recurrent disease. Overall 5-year survival rate was 58.3%. Successful resection of positive lymph node correlated with a survival advantage. CONCLUSIONS: Pretherapeutic laparoscopic assessment of patients with locally advanced cervical cancer offers valuable information for individualized treatment planning with minimal morbidity. This appears to be a therapeutic effect with resection of positive nodes followed by a tailored chemoradiation therapy.

[What is new in the surgical treatment of pelvic gynecologic cancers?]. / Actualités chirurgicales dans les cancers gynécologiques pelviens.

General tendency of modern cancerology is the research of adequacy between extent of disease and treatments. This concept is of course valid for gynaecology and we saw these last months the promising results of fertility-sparing surgery: in initial cervical cancers and in ovarian cancer with good prognosis. Actual Studies should define a clear attitude in patient less than 40 with initial endometrial cancer. At the same time, the development of laparoscopic surgery has continued in cervical cancer staging. If use of sentinel node in endometrial or vulvar cancers remains discussed as for its reliability, importance of staging was stressed for cervical cancer and initial ovarian cancer. Laparoscopic surgery is confirmed in patient at risk with endometrial cancer but it is necessary to stress efforts of French teams which still push back the technical limits of laparoscopic approach like pelvic exenteration or intra-peritoneal chemohyperthermia in advanced ovarian cancer. The adventure continues....