Proof of principle: Applicator-guided stereotactic IMRT boost in combination with 3D MRI-based brachytherapy in locally advanced cervical cancer.

To describe a new technique involving high-precision stereotactic intensity-modulated radiation therapy (IMRT) boost in combination with intracavitary-interstitial (IC-IS) brachytherapy (BT) in cervical tumors that cannot be sufficiently covered by IC-IS-BT due to extensive residual disease and/or difficult topography at the time of BT. Three patients with stage IIIB-IVA cervical cancer had significant residual disease at the time of BT. MRI-guided IC-IS-BT (pulsed-dose rate) was combined with a stereotactic IMRT boost guided according to the BT applicator in situ, using cone beam CT. The planning aim dose (total external beam radiotherapy and BT) for the high-risk clinical target volume (HR-CTV) was D90 >70-85 Gy, whereas constraints for organs at risk were D2cm3 <70 Gy for rectum, sigmoid, and bowel and <90 Gy for bladder in terms of equivalent total dose in 2 Gy fractions. An IMRT boost adapted to the BT dose distribution was optimized to target the regions poorly covered by BT. HR-CTV doses of D90 >81 Gy were obtained in the central HR-CTV and D90 >69 Gy in the distal regions of HR-CTV. Image-guided set up of the IMRT boost with the applicator in situ was feasible. The dose plans were robust to intra-fraction uncertainties of 3 mm. Local control with acceptable morbidity was obtained at a followup of 3, 2.5, and 1 year, respectively. The combination of MRI-guided BT with an applicator-guided stereotactic IMRT boost is feasible. This technique seems to be useful in the few cases where HR-CTV coverage cannot be obtained even with IS-IC-BT.

Assenholt MS ，Vestergaard A ，Kallehauge JF ，Mohamed S ，Nielsen SK ，Petersen JB ，Fokdal L ，Lindegaard JC ，Tanderup K ... -  《-》

A dose planning study on applicator guided stereotactic IMRT boost in combination with 3D MRI based brachytherapy in locally advanced cervical cancer.

Assenholt MS ，Petersen JB ，Nielsen SK ，Lindegaard JC ，Tanderup K ... -  《-》

Long term experience with 3D image guided brachytherapy and clinical outcome in cervical cancer patients.

To report our 10years' experience and learning curve of the treatment of cervical cancer patients with chemo radiotherapy and MRI (or CT in 9 selected patients) guided brachytherapy using pulsed dose rate (PDR) brachytherapy (BT). Hundred and seventy consecutive patients with cervical cancer FIGO stage IB-IVB (without metastases beyond the para-aortic nodal region) were treated in our institute between 2002 and 2012. Patients received external beam radiotherapy (nodal boost to the lymph nodes positive at diagnosis)±chemotherapy followed by a pulsed or low dose rate brachytherapy boost. MRI (or CT) images were taken with the applicator in situ. The first 16 patients were treated according to X-ray-based plans, optimized on MRI. High-risk CTV, intermediate-risk CTV, bladder, rectum and sigmoid were retrospectively contoured according to the GEC-ESTRO recommendations. In all other patients, treatment plans were optimized after delineation of the target volumes and organs at risk at MRI (or CT). Doses were converted to the equivalent dose in 2Gy (EQD2) by applying the linear quadratic model. The median age of the patients was 55years (range 16-88). 41% had stage III or IV disease. Of the 170 patients, 91 patients had on imaging metastatic lymph nodes at diagnosis (62 patients pelvic lymph node involvement and 29 para-aortic). In 27 (16%) patients the intracavitary technique was combined with interstitial brachytherapy. The mean D90 and D100 for the high-risk CTV were 84.8±8.36Gy and 67.5±6.29Gy for the entire patient group. Mean D90 and D100 values for the IR CTV were 68.7±5.5Gy and 56.5±6.25Gy. There was an important learning curve between both patient groups, with an increase in mean D90 of 75.8Gy for the first 16 patients compared to 85.8Gy for the second group. At the same time, the mean dose to 2cm3 of bladder and sigmoid decreased from 86.1Gy to 82.7Gy and from 70Gy to 61.7Gy, respectively. At a median follow-up of 37months (range 2-136months), local control rate for all patients was 96%, the regional control (pelvic and para-aortic) rate 81% and crude disease free survival rate 55%. The overall survival at 5years is 65%. The higher dose to the target volume resulted in an increase in local control from 88% in the first 16 patients compared to 97% in the second patient group. Regarding late toxicity, 21 patients (12%) presented grade 3-4 late morbidity. Rectal, urinary, sigmoid and vaginal morbidity was 5%, 6%, 2% and 5%, respectively. A correlation between rectal D2cm3 >65Gy and grade >3 late morbidity was found (p=0.006). Although the majority of the patients presented with locally advanced carcinoma, excellent local and regional control rates were achieved. Rectal, urinary, sigmoid and vaginal grade 3-4 morbidity was 5%, 6%, 2% and 5%, respectively. A correlation between rectal D2cm3 >65Gy and grade >3 late morbidity was found (p=0.006).

Ribeiro I ，Janssen H ，De Brabandere M ，Nulens A ，De Bal D ，Vergote I ，Van Limbergen E ... -  《-》

Three-dimensional dose accumulation in pseudo-split-field IMRT and brachytherapy for locally advanced cervical cancer.

Dose accumulation of split-field external beam radiotherapy (EBRT) and brachytherapy (BT) is challenging because of significant EBRT and BT dose gradients in the central pelvic region. We developed a method to determine biologically effective dose parameters for combined split-field intensity-modulated radiation therapy (IMRT) and image-guided BT in locally advanced cervical cancer. Thirty-three patients treated with split-field-IMRT to 45.0-51.2 Gy in 1.6-1.8 Gy per fraction to the elective pelvic lymph nodes and to 20 Gy to the central pelvis region were included in this study. Patients received six weekly fractions of high-dose rate BT to 6.5-7.3 Gy per fraction. A dose tracker software was developed to compute the equivalent dose in 2-Gy fractions (EQD2) to gross tumor volume (GTV), organs-at-risk and point A. Total dose-volume histogram parameters were computed on the 3D combined EQD2 dose based on rigid image registration. The dose accumulation uncertainty introduced by organ deformations between IMRT and BT was evaluated. According to International Commission on Radiation Unit and Measurement and GEC European Society for Therapeutic Radiology and Oncology recommendations, D98, D90, D50, and D2cm3 EQD2 dose-volume histogram parameters were computed. GTV D98 was 84.0 ± 26.5 Gy and D2cc was 99.6 ± 13.9 Gy, 67.4 ± 12.2 Gy, 75.0 ± 10.1 Gy, for bladder, rectum, and sigmoid, respectively. The uncertainties induced by organ deformation were estimated to be -1 ± 4 Gy, -3 ± 5 Gy, 2 ± 3 Gy, and -3 ± 5 Gy for bladder, rectum, sigmoid, and GTV, respectively. It is feasible to perform 3D EQD2 dose accumulation to assess high and intermediate dose regions for combined split-field IMRT and BT.

Sun B ，Yang D ，Esthappan J ，Garcia-Ramirez J ，Price S ，Mutic S ，Schwarz JK ，Grigsby PW ，Tanderup K ... -  《-》

Practically achievable maximum high-risk clinical target volume doses in MRI-guided intracavitary brachytherapy for cervical cancer: a planning study.

To explore maximum high-risk clinical target volume (HR-CTV) doses that can be practically achieved when organs at risk (OARs; bladder, rectum, and sigmoid) doses are allowed to equal current recommended thresholds in MRI-based intracavitary brachytherapy (BT) planning for cervical cancer. Planning MRI sets were retrieved for 21 patients who received pulsed-dose-rate BT boost. Plans were generated using manual optimization (MO) by adjusting dwell positions and times to obtain the prescribed HR-CTV isodose that includes 90% of target (D90) coverage of 35 Gy while limiting OAR doses to below recommended tolerances (prescribed dose target [TGT] plans). Additional planning was performed with automatic volume optimization (VO) to evaluate target coverage relative to the MO plans. The MO and VO approaches were then applied with the objective of obtaining the highest possible HR-CTV coverage when OAR doses were allowed to equal threshold tolerance values (maximized [MAX] plans). A two-tailed paired t test was performed to determine the statistical significance of the results; significance level set at p < 0.013. MO and VO planning techniques could conform HR-CTV D90 to the prescribed dose quite similarly for TGT plans. Using the MAX approach, the HR-CTV D90 could be increased by 30% and 37% for MO and VO, respectively, without exceeding OAR thresholds. Sigmoid and often rectum were the dose-limiting structures during MAX planning. Simple differences in the approach to volumetric MRI-based cervix BT treatment planning can impact HR-CTV D90. Consequently, dose escalation for MRI-guided cervix BT appears feasible in this manner should clinical circumstances warrant.

Menon G ，Huang F ，Sloboda R ，Pearcey R ，Ghosh S ... -  《-》