Renaud Mazeron

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.

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.

Neutrophilia in locally advanced cervical cancer: A novel biomarker for image-guided adaptive brachytherapy?

Objective To study the prognostic value of leucocyte disorders in a prospective cohort of cervical cancer patients receiving definitive chemoradiation plus image—guided adaptive brachytherapy (IGABT). Results 113 patients were identified. All patients received a pelvic irradiation concomitant with chemotherapy, extended to the para-aortic area in 13 patients with IVB disease. Neutrophilia and leukocytosis were significant univariate prognostic factors for poorer local failure-free survival (p = 0.000 and p = 0.002, respectively), associated with tumor size, high-risk clinical target volume (HR-CTV) and anemia. No effect was shown for distant metastases but leukocytosis and neutrophila were both poor prognostic factors for in-field relapses (p = 0.003 and p < 0.001). In multivariate analysis, HR-CTV volume (p = 0.026) and neutrophils count > 7,500/μl (p = 0.018) were independent factors for poorer survival without local failure, with hazard ratio (HR) of 3.1. Materials and methods We examined patients treated in our Institution between April 2009 and July 2015 by concurrent chemoradiation (45 Gy in 25 fractions +/− lymph node boosts) followed by a magnetic resonance imaging (MRI)-guided adaptive pulse-dose rate brachytherapy (15 Gy to the intermediate-risk clinical target volume). The prognostic value of pretreatment leucocyte disorders was examined. Leukocytosis and neutrophilia were defined as a leukocyte count or a neutrophils count exceeding 10,000 and 7,500/μl, respectively. Conclusions Neutrophilia is a significant prognostic factor for local relapse in locally advanced cervical cancer treated with MRI-based IGABT. This biomarker could help identifying patients with higher risk of local relapse and requiring dose escalation.

Intrafractional organs movement in three-dimensional image-guided adaptive pulsed-dose-rate cervical cancer brachytherapy: Assessment and dosimetric impact

PURPOSE To prospectively evaluate the intrafractional movements of organs at risk (OARs) and their dosimetric impact during the delivery of pulsed-dose-rate brachytherapy in cervical cancer. PATIENTS AND METHODS An MRI on Day 1 was used for treatment planning in 19 patients. CT scans were acquired at Days 1, 2, and 3 with delineation of the OARs. The MRI plan was transferred to each CT. The intersection volume between the 10 Gy isodose and the OARs were monitored, reflecting movement. Lower dose evaluated in the maximally exposed 0.1 cm(3) of an organ and lower dose evaluated in the maximally exposed 2 cm(3) of an organ (D(2cm3)) were evaluated on each CT and compared. Results were averaged considering that each CT reflected one-third of the treatment course to evaluate the delivered dose. RESULTS No major movements of the sigmoid and bladder were observed, whereas the rectum got significantly closer to the implant at Day 2. The consequence was an increase of 6% ± 5.3 (3.7 Gy, α/β = 3 Gy) of the delivered D(2cm3) from the planned dose, in contrast to 0.2% ± 6.1 for the bladder and 1.1% ± 6.4 for the sigmoid. The increase of the D(2cm3) of the rectum was reported in 17 patients, ranging from 0.4 to 9.4 Gy, leading to a 10.5% overcoming of the dose constraint (75 Gy). Similar tendencies were reported for lower dose evaluated in the maximally exposed 0.1 cm(3) of an organ. CONCLUSIONS A significant systematic variation was observed for the rectum (+3.7 Gy). As significant random variations were observed, caution should be exercised when the planned D(2cm3) is close to the dose constraints.

D2cm3/DICRU ratio as a surrogate of bladder hotspots localizations during image-guided adaptive brachytherapy for cervical cancer: Assessment and implications in late urinary morbidity analysis

PURPOSE To evaluate the efficiency and potential implications of the lowest dose evaluated in the maximally exposed 2cm(3) of the bladder/dose evaluated at the International Commission for Radiation Units and Measurements (ICRU) bladder point (D2cm(3)/DICRU) ratio as surrogate to locate the D2cm(3) in patients treated with MRI-guided adaptive brachytherapy for cervical cancer. METHODS AND MATERIALS The D2cm(3) area of the bladder was located in 69 patients, using the Digital Imaging and Communications in Medicine coordinates of its barycenter, with respect to the ICRU bladder point. The D2cm(3)/DICRU ratio was correlated with the longitudinal coordinate of the D2cm(3). Afterward, the ratio was used in a retrospective cohort of 216 patients to evaluate its impact in dose-effect analyses for late urinary incontinence. RESULTS The mean position of the D2cm(3) was 1.73±0.98 cm cranially, 0.59±0.65 cm backwardly, and 0.02±0.89 cm to the right of the ICRU point. It was located above the ICRU point in 95.7% of the patients. Its position was lower in patients with vaginal involvement at diagnosis (p=0.03). The D2cm(3)/DICRU ratio was correlated with the position of the D2cm(3) (R²=0.716, p<10(-6)). In speculating that a ratio greater than one would predict a D2cm(3) located above the ICRU point, the sensibility, specificity, positive, and negative predictive values were 95.2%, 100%, 100%, and 66.8%, respectively. Among the retrospective cohort, 85 patients had a ratio lower than 1.1, reflecting a D2cm(3) located in the lower bladder. In these patients, analyses showed significant dose relationship with Grade 2-4 incontinence (p=0.017), whereas no correlation was demonstrated in the remaining patients. CONCLUSIONS The D2cm(3)/DICRU ratio is a relevant surrogate to estimate the localization of the D2cm(3). Significant dose-effect correlations for incontinence were established in patients with low values for this ratio.

Image-guided adaptive brachytherapy in locally advanced cervical cancer: recent advances and perspectives.

Purpose of review Image-guided adaptive brachytherapy (IGABT) is a high-precision radiation that allows defining accurately treatment targets and optimizing their coverage whereas sparing efficiently the surrounding organs at risk. Ten years ago, in a will of harmonizing the reporting of brachytherapy, the Groupe Européen de Curiethérapie – European Society for Radiation Oncology (GEC-ESTRO) published recommendations on target definitions and dosimetric parameters. During the last years, clinical and dosimetric studies supporting their relevance led the International Commission on Radiation Units and Measurements to propose a report on prescribing and reporting. This review aims to highlight the recent advances in IGABT and its future developments. Recent findings Clinical evidence demonstrating the superiority of IGABT over radiographs-based brachytherapy is accumulating. In parallel, dose–volume effects have been established between dose–volume parameters and tumor response or the occurrence of late radiation morbidity. Preliminary studies indicate that planning aims could be adapted to clinical situations and cofactors. The first publications from the large studies led by the GEC-ESTRO enforce these findings. Summary A trend emerges toward a personalization of treatment with the adaptation of planning aims to prognostic features and the development of individualized applicators. Image-guidance modalities are developed with a better use of MRI or conversely the use of more accessible modalities such as transrectal ultrasound.

Improving safety in radiotherapy: The implementation of the Global Risk Analysis method

PURPOSE To report the application of the Global Risk Analysis (GRA), an innovative proactive risk analysis method, to a radiotherapy department. MATERIAL AND METHODS Analyses were conducted by a multidisciplinary working group with the support of a quality engineer. First, a mapping of hazardous situations was developed. For this, a double entry table was filled in, crossing the process of patient care divided into steps with a comprehensive list of pre-established hazards. The cells of the table represented interactions, which were, when relevant, considered as dangerous situations and then sorted by level of priority. For each high priority dangerous situation, scenarios were developed. Their criticality was assessed, using likelihood and severity scales, and a criticality matrix was used to allocate them into categories: acceptable (C1), tolerable (C2) and unacceptable (C3). Corrective actions were planned when relevant. Afterward, the criticality of the scenarios was reevaluated, leading to a residual risk mapping. RESULTS The number of high priority dangerous situations to analyze was 78, for which 205 scenarios were generated: 95 C1, 98 C2, and 12 C3 scenarios. Twenty-two corrective actions were planned. Mapping of residual risk resulted in the disappearance of C3 risks, leaving 18 C2 scenarios, for which six monitoring indicators were implemented. CONCLUSION The implementation of the GRA appeared feasible and led to the implementation of 22 corrective actions based on scenarios, without the occurrence of any incidents.

Brachytherapy in children with rhabdomyosarcomas of the nasolabial fold

Rhabdomyosarcomas (RMS) of the nasolabial fold can be difficult to manage surgically due to functional and cosmetic limitations. Therefore, brachytherapy (BT) has been proposed to improve local control while limiting the volume of irradiation as well as the extent of the surgical excision.

Preoperative image-guided brachytherapy in early stage cervical cancers

OBJECTIVE To examine the clinical results of a preoperative image-guided pulse-dose-rate brachytherapy (PDR-BT) in early stage cervical cancer. MATERIALS/METHODS We examined the outcome of consecutive patients with early stage cervical cancer undergoing preoperative image-guided PDR-BT between 2004 and 2013 because of risk factors (lymphovascular embols and/or tumour>2cm). The objective was to deliver 60Gy to 100% of the intermediate risk clinical target volume. Brachytherapy was followed, 6-8weeks later, by a radical hysterectomy/bilateral salpingo-oophorectomy plus pelvic +/- para-aortic lymph node dissection. Patients with positive lymph nodes had postoperative chemoradiation. RESULTS 77 patients met the above criteria of preoperative PDR-BT. On hysterectomy specimen, 54 (70.1%) presented a complete histological response. Four (5.2%) had a tumour residuum⩾1cm. Median follow-up was 46.8months. 5-Year disease-free survival (DFS) rate was 84.4%. Only one local recurrence was observed. The presence of lymph nodal metastases, a tumour size>3cm and a brachytherapy/surgery time interval⩾9weeks correlated with a poorer DFS. Six postoperative complications were encountered (7.8%). Total reference air kerma correlated with late vaginal toxicity (p=0.02). CONCLUSIONS A preoperative image-guided PDR-BT was safe and effective. Predictive factors for survival and toxicity were evidenced.

Gynecologic bleeding revealing vaginal metastasis of renal cell carcinoma

Vaginal metastases of renal cell carcinoma have been rarely described. We report a case of a 75-year old woman, who underwent radical right nephrectomy for a renal cell carcinoma. Tumour was classified pT3bN0M0 and grade III of Furhmann grading. One year later, scanner discovered mediastinal and lombo-aortic lymph nodes. She received 2 months of immunotherapy associated with bevacizumab, but stopped because of intolerance. She was readmitted in our institute for vaginal bleeding. Clinical investigations showed a vaginal mass and biopsy revealed a renal cell carcinoma metastasis. This case suggests that retrograde venous dissemination may be at the origin of vaginal metastasis of renal cell carcinoma and emphasized the preventive value of early ligature of renal vein.