R. Mazeron

Image guided brachytherapy in locally advanced cervical cancer: Improved pelvic control and survival in RetroEMBRACE, a multicenter cohort study

PURPOSE Image guided brachytherapy (IGBT) for locally advanced cervical cancer allows dose escalation to the high-risk clinical target volume (HRCTV) while sparing organs at risk (OAR). This is the first comprehensive report on clinical outcome in a large multi-institutional cohort. PATIENTS AND METHODS From twelve centres 731 patients, treated with definitive EBRT±concurrent chemotherapy followed by IGBT, were analysed. Kaplan-Meier estimates at 3/5years were calculated for local control (LC, primary endpoint), pelvic control (PC), overall survival (OS), cancer specific survival (CSS). In 610 patients, G3-4 late toxicity (CTCAEv3.0) was reported. RESULTS Median follow up was 43months, percent of patients per FIGO stage IA/IB/IIA 22.8%, IIB 50.4%, IIIA-IVB 26.8%. 84.8% had squamous cell carcinomas; 40.5% lymph node involvement. Mean EBRT dose was 46±2.5Gy; 77.4% received concurrent chemotherapy. Mean D90 HRCTV was 87±15Gy (EQD210), mean D2cc was: bladder 81±22Gy, rectum 64±9Gy, sigmoid 66±10Gy and bowel 64±9Gy (all EQD23). The 3/5-year actuarial LC, PC, CSS, OS were 91%/89%, 87%/84%, 79%/73%, 74%/65%. Actuarial LC at 3/5years for IB, IIB, IIIB was 98%/98%, 93%/91%, 79%/75%. Actuarial PC at 3/5years for IB, IIB, IIIB was 96%/96%, 89%/87%, 73%/67%. Actuarial 5-year G3-G5 morbidity was 5%, 7%, 5% for bladder, gastrointestinal tract, vagina. CONCLUSION IGBT combined with radio-chemotherapy leads to excellent LC (91%), PC (87%), OS (74%), CSS (79%) with limited severe morbidity.

Dose–volume effect relationships for late rectal morbidity in patients treated with chemoradiation and MRI-guided adaptive brachytherapy for locally advanced cervical cancer: Results from the prospective multicenter EMBRACE study

PURPOSE To establish dose volume-effect relationships predicting late rectal morbidity in cervix cancer patients treated with concomitant chemoradiation and MRI-guided adaptive brachytherapy (IBABT) within the prospective EMBRACE study. MATERIAL AND METHOD All patients were treated with curative intent according to institutional protocols with chemoradiation and IGABT. Reporting followed the GEC-ESTRO recommendations ( [Formula: see text] , [Formula: see text] ), applying bioeffect modeling (linear quadratic model) with equieffective doses (EQD23). Morbidity was scored according to the CTC-AE 3.0. Dose-effect relationships were assessed using comparisons of mean doses, the probit model and log rank tests on event-free periods. RESULTS 960 patients were included. The median follow-up was 25.4months. Twenty point one percent of the patients had grade 1 events, 6.0% grade 2, 1.6% grade 3 and 0.1%, grade 4. The mean DICRU, [Formula: see text] , and [Formula: see text] were respectively: 66.2±9.1Gy, 72.9±11.9Gy, and 62.8±7.6Gy. Increase of dose was associated with increase in severity of single endpoints and overall rectal morbidity (grade 1-4) (p<0.001-0.026), except for stenosis (p=0.24-0.31). The probit model showed significant relationships between the [Formula: see text] , [Formula: see text] , and DICRU and the probability of grade 1-4, 2-4, and 3-4 rectal events. The equieffective [Formula: see text] for a 10% probability for overall rectal grade⩾2 morbidity was 69.5Gy (p<0.0001). After sorting patients according to 6 [Formula: see text] levels, less favorable outcome was observed in the high dose subgroups, for bleeding, proctitis, fistula, and overall rectal morbidity. A [Formula: see text] ⩾75Gy was associated with a 12.5% risk of fistula at 3years versus 0-2.7% for lower doses (p>0.001). A [Formula: see text] <65Gy was associated with a two times lower risk of proctitis than [Formula: see text] ⩾65Gy. CONCLUSIONS Significant correlations were established between late rectal morbidity, overall and single endpoints, and dose-volume ( [Formula: see text] , [Formula: see text] ) and dose-point (DICRU) parameters. A [Formula: see text] ⩽65Gy is associated with more minor and less frequent rectal morbidity, whereas a [Formula: see text] ⩾75Gy is associated with more major and more frequent rectal morbidity.

Adaptive 3D Image-Guided Brachytherapy: A Strong Argument in the Debate on Systematic Radical Hysterectomy for Locally Advanced Cervical Cancer

PURPOSE To evaluate the outcomes of patients with locally advanced cervical cancer treated with three-dimensional image-guided brachytherapy (IGABT) after concomitant chemoradiation (CCRT). MATERIALS AND METHODS Data from patients treated with CCRT followed by magnetic resonance imaging-guided or computed tomography-guided pulsed-dose-rate brachytherapy, performed according to the Groupe Européen de Curiethérapie-European Society for Radiotherapy and Oncology guidelines, were reviewed. At first, stage I or II patients systematically underwent radical hysterectomy or were offered a randomized study evaluating hysterectomy. Then, hysterectomy was limited to salvage treatment. RESULTS Of 163 patients identified, 27% had stage IB, 57% had stage II, 12% had stage III, and 3% had stage IVA disease. The mean dose delivered (in 2-Gy dose equivalents) to 90% of the high-risk clinical target volume was 78.1 ± 9.6 Gy, whereas the doses delivered to organs at risk were maintained under the usual thresholds. Sixty-one patients underwent a hysterectomy. Macroscopic residual disease was found in 13 cases. With a median follow-up of 36 months (range, 5-79 months), 45 patients had relapsed. The 3-year overall survival rate was 76%. Local and pelvic control rates were 92% and 86%, respectively. According to the Common Toxicity Criteria 3.0, 7.4% of patients experienced late grade 3 or 4 toxicity. Most of those had undergone postradiation radical surgery (2.9% vs. 14.8; p = .005). CONCLUSION IGABT combined with CCRT provides excellent locoregional control rates with low treatment-related morbidity, justifying the elimination of hysterectomy in the absence of obvious residual disease. Distant metastasis remains an important first relapse and may warrant more aggressive systemic treatment.

Current concepts of management in radiotherapy for head and neck squamous-cell cancer

Radiotherapy plays a key role in the management of early stage and locally advanced head and neck squamous-cell carcinomas (HNSCC) either alone or, more frequently combined with surgery and/or chemotherapy. Several approaches have been developed to improve its efficacy while maintaining acceptable toxicities, such as altered fractionated radiotherapy or concomitant chemoradiotherapy which have both improved the anti-tumor efficacy of radiotherapy. Of particular interest is concomitant chemoradiotherapy (CT-RT) which is the most commonly used approach in locally advanced disease. Taxanes and platinum-based induction chemotherapy could constitute an option in the treatment of locally advanced HNSCC and its contribution before concomitant RT-CT is currently under investigation. More recently, epidermal growth factor receptor (EGFr) molecular targeting with cetuximab combined with radiotherapy has been successfully tested in a large randomized trial and this combination constitutes a new option, especially for patients with medical co-morbidities. Finally management of treatment related acute or late toxicity remains an important issue and in the last decade major achievements have been obtained in this field especially using intensity modulated radiotherapy (IMRT).

Effect of tumor dose, volume and overall treatment time on local control after radiochemotherapy including MRI guided brachytherapy of locally advanced cervical cancer.

BACKGROUND AND PURPOSE Currently, there is no consensus on dose prescription in image guided adaptive brachytherapy (IGABT) in locally advanced cervical cancer. The purpose of this study was to provide evidence based recommendations for tumor dose prescription based on results from a multi-center patient series (retroEMBRACE). MATERIALS AND METHODS This study analyzed 488 locally advanced cervical cancer patients treated with external beam radiotherapy±chemotherapy combined with IGABT. Brachytherapy contouring and reporting was according to ICRU/GEC-ESTRO recommendations. The Cox Proportional Hazards model was applied to analyze the effect on local control of dose-volume metrics as well as overall treatment time (OTT), dose rate, chemotherapy, and tumor histology. RESULTS With a median follow up of 46months, 43 local failures were observed. Dose (D90) to the High Risk Clinical Target Volume (CTVHR) (p=0.022, HR=0.967 per Gy) was significant for local control, whereas increasing CTVHR volume (p=0.004, HR=1.017 per cm3), and longer OTT (p=0.004, HR=1.023 per day) were associated with worse local control. Histology (p=0.084), chemotherapy (p=0.49) and dose rate (p=1.00) did not have significant impact on local control. Separate analyses according to stage of disease showed that dose to CTVHR, residual gross tumor volume (GTVres), and Intermediate Risk CTV (CTVIR) has significant impact on local control. CONCLUSION CTVHR dose of ⩾85Gy (D90) delivered in 7weeks provides 3-year local control rates of >94% in limited size CTVHR (20cm3), >93% in intermediate size (30cm3) and >86% in large size (70cm3) CTVHR. CTVIR and GTVres dose of ⩾60Gy and ⩾95Gy (D98) leads to similar local control. A dose of 5Gy (CTVHR) is required to compensate an increase of OTT by one week. Increased CTVHR volume by 10cm3 requires additional 5Gy for equivalent local control.

Image guided adaptive brachytherapy with combined intracavitary and interstitial technique improves the therapeutic ratio in locally advanced cervical cancer: Analysis from the retroEMBRACE study

BACKGROUND AND PURPOSE Image guided adaptive brachytherapy (IGABT) using intracavitary applicators (IC) has led to a significant improvement of local control in locally advanced cervical cancer (LACC). Further improvement has been obtained with combined intracavitary/interstitial (IC/IS) applicators. The aim of this analysis was to evaluate the impact on local control and late morbidity of application of combined IS/IC brachytherapy in a large multicentre population. MATERIAL/METHODS 610 patients with LACC from the retroEMBRACE study were included. Patients were divided into an IC group (N=310) and an IC/IS group (N=300). The IC/IS group was defined from the time point, when a centre performed IC/IS brachytherapy in more than 20% of cases. RESULTS With systematic usage of IC/IS the D90 of CTVHR increased from 83±14Gy to 92±13Gy (p<0.01). No difference in doses to organs at risk was found. The 3-year local control rate in patients having a CTVHR volume⩾30cm3 was 10% higher (p=0.02) in the IC/IS group. No difference was found for CTVHR<30cm3 (p=0.50). No significant difference in late morbidity was found between the IC/IS group and IC group. CONCLUSION Combined IC/IS brachytherapy improves the therapeutic ratio in LACC by enabling a tumour specific dose escalation resulting in significantly higher local control in large tumours without adding treatment related late morbidity.

Clinical evidence on PET–CT for radiation therapy planning in cervix and endometrial cancers

PET-CT plays an increasing role in the diagnosis and treatment of gynaecological cancers. In cervix cancer, whilst MRI remains the best imaging technique for initial primary tumor staging, PET-CT has been showed to be a highly sensitive method to determine lymph node status, except in patients with early-stage cervical cancer where PET-CT cannot replace surgical exploration of pelvic lymph nodes. In patients with advanced cervical cancer, PET-CT has the potential of showing lymph node metastasis not only within the pelvis, but also outside the pelvis, more particularly in the para-aortic area. PET-CT has also been described as a useful tool in 3-D-based adaptative brachytherapy. In endometrial cancer, the issues are different, as the recent decade has seen a therapeutic decrease in early-stage disease, especially in postoperative radiation therapy, whilst more advanced disease have been approached with more aggressive treatments, integrating chemotherapy and external beam radiotherapy. Lymph node status is also an important issue and PET-Scan may replace lymph node surgical procedure particularly in obese patients.

Current state of knowledge regarding the use of antiangiogenic agents with radiation therapy

Angiogenesis has been a central theme of oncologic research for several years. Recently, improved understanding of its mechanisms has led to the development of several antiangiogenic agents. Some have demonstrated their effectiveness in large randomized studies; however, no antiangiogenic agent has yet been approved for treatment in combination with radiotherapy. Numerous preclinical studies and a few small clinical trials have recently reported encouraging results. The objective of this article is to review the concept of targeted antiangiogenic agents and the early clinical results of their use in combination with radiation therapy.

Concurrent Etoposide, Steroid, High-dose Ara-C and Platinum chemotherapy with radiation therapy in localised extranodal natural killer (NK)/T-cell lymphoma, nasal type

PURPOSE Radiation combined with chemotherapy has recently been proposed to treat patients with localised extranodal natural killer (NK)/T lymphoma (ENKTL), nasal type. However, the modalities of the chemoradiotherapy combination and drug choices remain a matter of debate. We conducted a concurrent chemoradiotherapy (CCRT) study with the ESHAP (Etoposide, Steroid, High-dose Ara-C and Platinum) regimen. METHODS An induction phase with two upfront courses of CCRT delivering a 40Gy dose of radiation concurrently with two cycles of the ESHAP chemotherapy regimen, followed by a consolidation phase with 2-3 cycles of ESHAP chemotherapy alone. RESULTS Thirteen patients with localised ENKTL nasal type were enrolled between January 2005 and December 2014. The median age was 62years. Ten and three patients had Ann Arbor stage IE and IIE disease, respectively. They all completed the induction CCRT phase. A median of two consolidation ESHAP cycles were delivered. During consolidation, 8/13 (62%) patients had a reduction in the number of chemotherapy cycles or reduced chemotherapy doses, due to haematologically adverse events. The other five patients (38%) received the full number of ESHAP cycles of chemotherapy scheduled without a dose reduction. All but one patient (92%) experienced grade 3-4 haematological toxicity. The main non-haematological grade 3-4 toxicity was mucositis in 6/13 (46%) patients. All but one patient (92%) achieved a complete remission. Two-year overall survival was 72%. CONCLUSIONS With optimal management of the specific toxicities induced by this treatment modality, CCRT with the ESHAP regimen yielded high efficacy against localised ENKTL, nasal type.

Angiogenèse et radiothérapie : tout ce qu’un oncologue radiothérapeute doit savoir

Angiogenesis is a crucial requirement for tumorogenesis, providing oxygen and nutrient supply necessary for tumor growth and metastasis. This is a complex phenomenon regulated by many factors that can now be targeted by novel anti-cancer therapies. Antiangiogenic approaches have shown positive results in clinical trials and are now approved as standard of care in medical oncology. Many clinical trials are evaluating antiangiogenic agents in association with radiotherapy. This review aims to summarize the knowledge useful to the understanding of these novel therapies and their potential in combination with radiotherapy.