Nicole Nesvacil

Clinical outcome of protocol based image (MRI) guided adaptive brachytherapy combined with 3D conformal radiotherapy with or without chemotherapy in patients with locally advanced cervical cancer

Background To analyse the overall clinical outcome and benefits by applying protocol based image guided adaptive brachytherapy combined with 3D conformal external beam radiotherapy (EBRT) ± chemotherapy (ChT). Methods Treatment schedule was EBRT with 45–50.4 Gy ± concomitant cisplatin chemotherapy plus 4 × 7 Gy High Dose Rate (HDR) brachytherapy. Patients were treated in the “protocol period” (2001–2008) with the prospective application of the High Risk CTV concept (D90) and dose volume constraints for organs at risk including biological modelling. Dose volume adaptation was performed with the aim of dose escalation in large tumours (prescribed D90 > 85 Gy), often with inserting additional interstitial needles. Dose volume constraints (D2cc) were 70–75 Gy for rectum and sigmoid and 90 Gy for bladder. Late morbidity was prospectively scored, using LENT/SOMA Score. Disease outcome and treatment related late morbidity were evaluated and compared using actuarial analysis. Findings One hundred and fifty-six consecutive patients (median age 58 years) with cervix cancer FIGO stages IB–IVA were treated with definitive radiotherapy in curative intent. Histology was squamous cell cancer in 134 patients (86%), tumour size was >5 cm in 103 patients (66%), lymph node involvement in 75 patients (48%). Median follow-up was 42 months for all patients. Interstitial techniques were used in addition to intracavitary brachytherapy in 69/156 (44%) patients. Total prescribed mean dose (D90) was 93 ± 13 Gy, D2cc 86 ± 17 Gy for bladder, 65 ± 9 Gy for rectum and 64 ± 9 Gy for sigmoid. Complete remission was achieved in 151/156 patients (97%). Overall local control at 3 years was 95%; 98% for tumours 2–5 cm, and 92% for tumours >5 cm (p = 0.04), 100% for IB, 96% for IIB, 86% for IIIB. Cancer specific survival at 3 years was overall 74%, 83% for tumours 2–5 cm, 70% for tumours >5 cm, 83% for IB, 84% for IIB, 52% for IIIB. Overall survival at 3 years was in total 68%, 72% for tumours 2–5 cm, 65% for tumours >5 cm, 74% for IB, 78% for IIB, 45% for IIIB. In regard to late morbidity in total 188 grade 1 + 2 and 11 grade 3 + 4 late events were observed in 143 patients. G1 + 2/G3 + 4 events for bladder were n = 32/3, for rectum n = 14/5, for bowel (including sigmoid) n = 3/0, for vagina n = 128/2, respectively. Interpretation 3D conformal radiotherapy ± chemotherapy plus image (MRI) guided adaptive intracavitary brachytherapy including needle insertion in advanced disease results in local control rates of 95–100% at 3 years in limited/favourable (IB/IIB) and 85–90% in large/poor response (IIB/III/IV) cervix cancer patients associated with a moderate rate of treatment related morbidity. Compared to the historical Vienna series there is relative reduction in pelvic recurrence by 65–70% and reduction in major morbidity. The local control improvement seems to have impact on CSS and OS. Prospective clinical multi-centre studies are mandatory to evaluate these challenging mono-institutional findings.

A multicentre comparison of the dosimetric impact of inter- and intra-fractional anatomical variations in fractionated cervix cancer brachytherapy

Background and purpose To compare the dosimetric impact of organ and target variations relative to the applicator for intracavitary brachytherapy by a multicentre analysis with different application techniques and fractionation schemes. Material and methods DVH data from 363 image/contour sets (120 patients, 6 institutions) were included for 1–6 fractions per patient, with imaging intervals ranging from several hours to ∼20 days. Variations between images acquired within one (intra-application) or between consecutive applicator insertions (inter-application) were evaluated. Dose plans based on a reference MR or CT image series were superimposed onto subsequent image sets and D2cm3 for the bladder, rectum and sigmoid and D90 for HR CTV were recorded. Results For the whole sample, the systematic dosimetric variations for all organs at risk, i.e. mean variations of D2cm3, were found to be minor (<5%), while random variations, i.e. standard deviations were found to be high due to large variations in individual cases. The D2cm3 variations (mean ± 1SD) were 0.6 ± 19.5%, 4.1 ± 21.7% and 1.6 ± 26.8%, for the bladder, rectum and sigmoid. For HR CTV, the variations of D90 were found to be −1.1 ± 13.1% for the whole sample. Grouping of the results by intra- and inter-application variations showed that random uncertainties for bladder and sigmoid were 3–7% larger when re-implanting the applicator for individual fractions. No statistically significant differences between the two groups were detected in dosimetric variations for the HR CTV. Using 20% uncertainty of physical dose for OAR and 10% for HR CTV, the effects on total treatment dose for a 4 fraction HDR schedule at clinically relevant dose levels were found to be 4–8 Gy EQD2 for OAR and 3 Gy EQD2 for HR CTV. Conclusions Substantial variations occur in fractionated cervix cancer BT with higher impact close to clinical threshold levels. The treatment approach has to balance uncertainties for individual cases against the use of repetitive imaging, adaptive planning and dose delivery.

Adaptive image guided brachytherapy for cervical cancer: A combined MRI-/CT-planning technique with MRI only at first fraction

Purpose To investigate and test the feasibility of adaptive 3D image based BT planning for cervix cancer patients in settings with limited access to MRI, using a combination of MRI for the first BT fraction and planning of subsequent fractions on CT. Material and methods For 20 patients treated with EBRT and HDR BT with tandem/ring applicators two sets of treatment plans were compared. Scenario one is based on the “gold standard” with individual MRI-based treatment plans (applicator reconstruction, target contouring and dose optimization) for two BT applications with two fractions each. Scenario two is based on one initial MRI acquisition with an applicator in place for the planning of the two fractions of the first BT application and reuse of the target contour delineated on MRI for subsequent planning of the second application on CT. Transfer of the target from MRI of the first application to the CT of the second one was accomplished by use of an automatic applicator-based image registration procedure. Individual dose optimization of the second BT application was based on the transferred MRI target volume and OAR structures delineated on CT. DVH parameters were calculated for transferred target structures (virtual dose from MRI/CT plan) and CT-based OAR. The quality of the MRI/CT combination method was investigated by evaluating the CT-based dose distributions on MRI-based target and OAR contours of the same application (real dose from MRI/CT plan). Results The mean difference between the MRI based target volumes (HR CTVMRI2) and the structures transferred from MRI to CT (HR CTVCT2) was −1.7 ± 6.6 cm3 (−2.9 ± 20.4%) with a median of −0.7 cm3. The mean difference between the virtual and the real total D90, based on the MRI/CT combination technique was −1.5 ± 4.3 Gy EQD2. This indicates a small systematic underestimation of the real D90. Conclusions A combination of MRI for first fraction and subsequent CT based planning is feasible and easy when automatic applicator-based image registration and target transfer are technically available. The results show striking similarity to fully MRI-based planning in cases of small tumours and intracavitary applications, both in terms of HR CTV coverage and respecting of OAR dose limits. For larger tumours and complex applications, as well as situations with unfavourable OAR topography, especially for the sigmoid, MRI based adaptive BT planning remains the superior method.

Uncertainties in image guided adaptive cervix cancer brachytherapy: Impact on planning and prescription

IntroductionImage guided adaptive brachytherapy based on 3D volumetricimaging has been implemented into clinical practice in an increas-ing number of institutions during the last decade [1–5], and thisadvanced technique is gradually replacing radiography-basedbrachytherapy. In particular, with the use of MRI guidance [6],itis possible to individually tailor the brachytherapy dose accordingto an adaptive approach taking the EBRT tumour response into ac-count as well as the initial tumour extension as defined in GEC ES-TRO recommendations [7]. With the introduction of 3D volumetricimage based brachytherapy it became possible to report doses interms of DVH parameters according to GEC ESTRO recommenda-tions [8]. New ICRU/GEC ESTRO recommendations on intracavitarybrachytherapy in cervix cancer define further developments withinvolumetric imaging reporting (under publication). Further effortsare related to refining target definition with the incorporation offunctional imaging [9,10]. CT and MR image based brachytherapyhas significantly improved the precision of dose reporting for tu-mour and OARs. 2D and radiography-based reporting has reliedon point A and ICRU bladder and rectum point doses in most insti-tutions [11,12]. These points have significant limitations as surro-gates for target and OAR [13], and the relation between point dosesand DVH parameters is associated with significant variations of40% (SD) and 20% (SD) for target (HR CTV) and OARs (rectum, blad-der), respectively [14]. Improved assessment of dose has signifi-cantly improved the possibilities to assess dose response fortumour and OARs in cervix cancer [15–18].While uncertainties related to 3D image based EBRT have beeninvestigated in detail during decades [19–26], there has so far beena limited overview of uncertainties related to 3D volumetric imageguided brachytherapy. There have been ‘‘dogmas’’ that uncertain-ties in brachytherapy are negligible based on the observation thatthe applicator, tumour and surrounding tissues represent a stablesystem. However, brachytherapy dose gradients are significantand geometric uncertainties can potentially lead to significantuncertainties which cannot be neglected. This issue of Radiother-apy and Oncology presents for the first time a comprehensive col-lection of papers focussing on uncertainties in image guidedgynaecological brachytherapy. The papers represent an importantstep forward in terms of understanding the magnitude and impor-tance of various uncertainties. This is the prerequisite for movingforward with focus on decreasing the most relevant variationsfor the improvement of clinical outcome.Variations and uncertainties in gynaecological brachytherapyA complete description of variations and uncertainties in brach-ytherapy takes into account every step in the brachytherapy proce-dure from calibration to dose delivery. Uncertainties in cervixcancer brachytherapy are mainly related to: source calibration,dose and DVH calculation, reconstruction of applicators, contour-ing, intra- and inter-fraction uncertainties, and dose delivery(Table 1). Source calibration and dose calculation uncertaintiesare extensively evaluated and recently described in a comprehen-sive review [27]. Dose calculationin the pelvic region with high en-ergy sources does not suffer fromheterogeneity considerationsandhas high accuracy. Including DVH calculation [28] this is expectedto be within 3% (SD). Further calculation uncertainties are relatedto the calculation of biological equivalent dose [29]. Geometricuncertainties originating from afterloader source positioning aswell as reconstruction of the applicator have been dealt with innumerous papers, and dosimetric uncertainties related to applica-tor reconstruction and source positioning have been evaluated tobe less than 4% (SD) [30–35]. Uncertainties related to dose accu-mulation across several brachytherapy fractions have not previ-ously been evaluated in brachytherapy, but are now addressed intwo papers in this journal issue [36,37]. In clinical practice, doseaccumulation across several fractions is currently done by DVHaddition (previously called the ‘‘worst case scenario’’) which isknown to result in potential overestimation of dose [8]. However,this overestimation seems to be of minor importance in the bladderand likely also in the rectum [37]. More challenging, large inter-frac-tion deformations have been found in the sigmoid colon [36,38].Thiscurrently imposes significant problems to perform reliable dose accu-mulation in this organ. Inter- and intra-fraction motion may be partof the explanation that dose response relationships for sigmoid re-lated morbidity have not yet been established [16].The dosimetric impact of contouring uncertainties in gynaeco-logical brachytherapy is for the first time evaluated in this journal

Local recurrences in cervical cancer patients in the setting of image-guided brachytherapy: a comparison of spatial dose distribution within a matched-pair analysis.

Purpose It has been shown that a cumulative dose of ⩾87 Gy (EQD2) of external beam radiotherapy (EBRT) and image guided adaptive brachytherapy (IGABT) to the high risk clinical target volume (HR CTV) confer a local control rate >95% in locally advanced cervical cancer. This study examines the dose distribution within the HR CTV and intermediate (IR) CTV in patients with cervical cancer treated with definitive EBRT +/− concomitant chemotherapy and MRI-based IGABT between patients with local recurrence (LR) and patients in continuous complete local remission (CCLR). Material and methods From 1998 to 2010, 265 patients were treated with definitive EBRT +/− concomitant chemotherapy and IGABT. Twenty-four LRs were documented. For the statistical analysis all patients with LR were matched to patients in CCLR from our database according to the following criteria: FIGO stage, histology, lymph node status, tumour size and chemotherapy. DVH parameters (D50, D90, D98, D100) were reported for HR CTV and IR CTV. In order to report the minimum dose in the region where the recurrence occurred, the HR CTV/IR CTV were divided into four quadrants on transversal planes. The minimum dose at the HR CTV/IR CTV contour was measured (within the corresponding quadrant closest to the LR) in the treatment planning system. A mean minimum point dose (MPD) was calculated by averaging these measurements on four consecutive slices at the level of the recurrence for each of the 4 brachytherapy fractions. EQD2 doses were calculated by summation of all BT and external beam therapy fractions. For each matched patient in the control group the measurements were performed on the same quadrant and at the same level. Results Sufficient image data were available for 21 LRs. Eight central failures and 13 non-central failures were observed. The mean D90 and D100 for HR CTV were 77 Gy and 61 Gy for patients with LR and 95 Gy and 71 Gy for patients in CCLR, respectively (p < 0.01). The MPD for HR CTV was 72 Gy for patients in the LR arm and 99 Gy for patients in the CCLR arm (p < 0.01). In the LR arm seven patients had a D90 for HR CTV ⩾87 Gy, however, in only three patients the MPD was ⩾87 Gy. Conclusion This study demonstrated significant differences in local outcome according to the delivered dose. In 85% of the LRs systematic low dose regions with less than 87 Gy were found at HR CTV contour. Systematic low dose regions leading to local recurrence could be detected even if a D90 HR CTV ⩾87 Gy was applied. In addition to DVH parameters, inspection of the spatial dose distribution remains a key point in dose prescription.

Uncertainty analysis for 3D image-based cervix cancer brachytherapy by repetitive MR imaging: assessment of DVH-variations between two HDR fractions within one applicator insertion and their clinical relevance.

PURPOSE To investigate dosimetric uncertainties of MRI-based cervix cancer brachytherapy, when applying two HDR fractions for each applicator insertion and their clinical relevance. METHODS 21 patients with 84 MRI-examinations and fractions were investigated. After insertion of the MRI compatible tandem-ring applicator, an MRI-set was recorded and the treatment plan optimised for the first fraction. Prior to the second fraction 16-20 h later a second MRI-set was recorded, and the dose distribution from the plan of the previous day superimposed and analysed. The same procedure was repeated for fractions 3 and 4. Dose from EBRT and brachytherapy was normalised to 2 Gy-fractionation (EQD2), added up to a total dose, and compared to a calculated total dose if only 1 MRI-examination per insertion is available. RESULTS The total D(90) for High risk (HR) CTV was 1.2±2.7 Gy(αβ10) (1±3%) (mean±1SD) lower by individual MRI-evaluation of each fraction compared to 1 MRI per insertion. The D(2cm(3)) increased by 0.7±4.7 Gy(αβ3) (1±6%) for bladder, 1.1±2.4 Gy(αβ3) (2±4%) for rectum and decreased by 0.8±3.4 Gy(αβ3) (1±5%) for sigmoid. For HR CTV the individual approach did not identify any case with a decrease of D(90) >5 Gy(αβ10). For the bladder 3 cases, for the rectum no case and for the sigmoid 1 case was identified with an increase of D(2cm(3)) >5 Gy(αβ3). For the bladder all dose variations of more than 5 Gy(αβ3) could have been avoided by ensuring a constant bladder filling. Individual MRI-evaluation did not determine any case where dose constraints were not fulfilled. CONCLUSIONS For the treatment schedule as applied in this study, geometric differences between applicator, target and OAR result in overall dosimetric changes, which seem to be of minor relevance in regard to clinical dose volume constraints applied at present.

High-risk clinical target volume delineation in CT-guided cervical cancer brachytherapy: Impact of information from FIGO stage with or without systematic inclusion of 3D documentation of clinical gynecological examination

Abstract Purpose. The aim of the study was to improve computed tomography (CT)-based high-risk clinical target volume (HR CTV) delineation protocols for cervix cancer patients, in settings without any access to magnetic resonance imaging (MRI) at the time of brachytherapy. Therefore the value of a systematic integration of comprehensive three-dimensional (3D) documentation of repetitive gynecological examination for CT-based HR CTV delineation protocols, in addition to information from FIGO staging, was investigated. In addition to a comparison between reference MRI contours and two different CT-based contouring methods (using complementary information from FIGO staging with or without additional 3D clinical drawings), the use of standardized uterine heights was also investigated. Material and methods. Thirty-five cervix cancer patients with CT- and MR-images and 3D clinical drawings at time of diagnosis and brachytherapy were included. HR CTVstage was based on CT information and FIGO stage. HR CTVstage + 3Dclin was contoured on CT using FIGO stage and 3D clinical drawing. Standardized HR CTV heights were: 1/1, 2/3 and 1/2 of uterine height. MRI-based HR CTV was delineated independently. Resulting widths, thicknesses, heights, and volumes of HR CTVstage, HR CTVstage + 3Dclin and MRI-based HR CTV contours were compared. Results. The overall normalized volume ratios (mean± SD of CT/MRIref volume) of HR CTVstage and HR stage + 3Dclin were 2.6 (± 0.6) and 2.1 (± 0.4) for 1/1 and 2.3 (± 0.5) and 1.8 (± 0.4), for 2/3, and 1.9 (± 0.5) and 1.5 (± 0.3), for 1/2 of uterine height. The mean normalized widths were 1.5 ± 0.2 and 1.2 ± 0.2 for HR CTVstage and HR CTVstage + 3Dclin, respectively (p < 0.05). The mean normalized heights for HR CTVstage and HR CTVstage + 3Dclin were both 1.7 ± 0.4 for 1/1 (p < 0.05.), 1.3 ± 0.3 for 2/3 (p < 0.05) and 1.1 ± 0.3 for 1/2 of uterine height. Conclusion. CT-based HR CTV contouring based on FIGO stage alone leads to large overestimation of width and volume. Target delineation accuracy can systematically improve through incorporation of additional information from comprehensive 3D documentation of repetitive gynecological examination in the contouring protocol, and thus help to improve the accuracy of dose optimization in settings with limited access to imaging facilities at the time of brachytherapy. If CT information is only available, minimum 2/3 of uterine height may be a good surrogate for the height of HR CTV.

Transrectal ultrasound for image-guided adaptive brachytherapy in cervix cancer - An alternative to MRI for target definition?

PURPOSE To compare the maximum high risk clinical target volume (CTVHR) dimensions and image quality between magnetic resonance imaging (MRI), transrectal ultrasound (TRUS) and computed tomography (CT) in image guided adaptive brachytherapy (IGABT) of locally advanced cervical cancer. MATERIAL AND METHODS All patients with locally advanced cervical cancer treated with radiochemotherapy and IGABT between 09/2012-05/2013 were included in this study. T2-weighted MRI (1.5 tesla), TRUS and CT were performed before (MRIpreBT, TRUSpreBT) and/or after (MRIBT, TRUSBT and CTBT) insertion of the applicator. 3D TRUS image acquisition was done with a customized US stepper device and software. The HR CTV was defined on 3D image sequences acquired with different imaging modalities by one blinded observer, in accordance to the GEC-ESTRO recommendations for MRI-based target volume delineation, as the complete cervical mass including the tumour, any suspicious areas of parametrial involvement and the normal cervical stroma. Maximum HR CTV width and thickness were measured on transversal planes. Image quality was classified using the following scoring system: Grade 0: not depicted, Grade 1: inability to discriminate, margin not recognizable, Grade 2: fair discrimination, margin indistinct, Grade 3: excellent discrimination, margin distinct. Descriptive statistics, mean differences between the groups, with MRIBT as reference, and a paired t-test were calculated. RESULTS Images from 19 patients (FIGO IB: 3, IIB: 9, IIIB: 5, IVB: 2) were available for analysis. The mean difference in maximum HR CTV width of TRUSBT, TRUSpreBT, MRIpreBT, CTBT to MRIBT was 0.0mm±4.7 (n.s.), -1.1mm±5.6 (n.s.), 0.7mm±6.4 (n.s.) and 13.8mm±6.7 (p<0.001). The mean difference in maximum HR CTV thickness of TRUSBT, TRUSpreBT, MRIpreBT, CTBT to MRIBT was -3.4mm±5.9 (p=0.037), -3.4mm±4.2 (p<0.001), 2.0mm±6.1 (n.s.) and 13.9mm±6.3 (p<0.001). Mean scores of image quality of the target volume was 2.9 for TRUSpreBT, 2.3 for TRUSBT, 2.9 for MRIpreBT, 2.7 for MRIBT and 2.1 for CTBT. CONCLUSION For the assessment of the HR CTV in IGABT of cervical cancer, TRUS is within the intraobserver variability of MRI. TRUS is superior to CT as it yields systematically smaller deviations from MRI, with good to excellent image quality. Small differences of TRUS HR CTV thickness are likely related to differences in image slice orientation and compression of the cervix by the TRUS probe before insertion of the brachytherapy applicator.

Value of Magnetic Resonance Imaging Without or With Applicator in Place for Target Definition in Cervix Cancer Brachytherapy

PURPOSE To define, in the setting of cervical cancer, to what extent information from additional pretreatment magnetic resonance imaging (MRI) without the brachytherapy applicator improves conformity of CT-based high-risk clinical target volume (CTVHR) contours, compared with the MRI for various tumor stages (International Federation of Gynecology and Obstetrics [FIGO] stages I-IVA). METHODS AND MATERIALS The CTVHR was contoured in 39 patients with cervical cancer (FIGO stages I-IVA) (1) on CT images based on clinical information (CTVHR-CTClinical) alone; and (2) using an additional MRI before brachytherapy, without the applicator (CTVHR-CTpre-BT MRI). The CT contours were compared with reference contours on MRI with the applicator in place (CTVHR-MRIref). Width, height, thickness, volumes, and topography were analyzed. RESULTS The CT-MRIref differences hardly varied in stage I tumors (n=8). In limited-volume stage IIB and IIIB tumors (n=19), CTVHR-CTpre-BT MRI-MRIref volume differences (2.6 cm(3) [IIB], 7.3 cm(3) [IIIB]) were superior to CTVHR-CTClinical-MRIref (11.8 cm(3) [IIB], 22.9 cm(3) [IIIB]), owing to significant improvement of height and width (P<.05). In advanced disease (n=12), improved agreement with MR volume, width, and height was achieved for CTVHR-CTpre-BT MRI. In 5 of 12 cases, MRIref contours were partly missed on CT. CONCLUSIONS Pre-BT MRI helps to define CTVHR before BT implantation appropriately, if only CT images with the applicator in place are available for BT planning. Significant improvement is achievable in limited-volume stage IIB and IIIB tumors. In more advanced disease (extensive IIB to IVA), improvement of conformity is possible but may be associated with geographic misses. Limited impact on precision of CTVHR-CT is expected in stage IB tumors.

Can reduction of uncertainties in cervix cancer brachytherapy potentially improve clinical outcome

AIM The aim of this study was to quantify the impact of different types and magnitudes of dosimetric uncertainties in cervix cancer brachytherapy (BT) on tumour control probability (TCP) and normal tissue complication probability (NTCP) curves. MATERIALS AND METHODS A dose-response simulation study was based on systematic and random dose uncertainties and TCP/NTCP models for CTV and rectum. Large patient cohorts were simulated assuming different levels of dosimetric uncertainties. TCP and NTCP were computed, based on the planned doses, the simulated dose uncertainty, and an underlying TCP/NTCP model. Systematic uncertainties of 3-20% and random uncertainties with a 5-30% standard deviation per BT fraction were analysed. RESULTS Systematic dose uncertainties of 5% lead to a 1% decrease/increase of TCP/NTCP, while random uncertainties of 10% had negligible impact on the dose-response curve at clinically relevant dose levels for target and OAR. Random OAR dose uncertainties of 30% resulted in an NTCP increase of 3-4% for planned doses of 70-80Gy EQD2. CONCLUSION TCP is robust to dosimetric uncertainties when dose prescription is in the more flat region of the dose-response curve at doses >75Gy. For OARs, improved clinical outcome is expected by reduction of uncertainties via sophisticated dose delivery and treatment verification.