To compare dose-volume histogram parameters of standard Point A and magnetic resonance imaging-based three-dimensional optimized dose plans in 21 consecutive patients who underwent pulsed-dose-rate ...brachytherapy (PDR-BT) for locally advanced cervical cancer.
All patients received external beam radiotherapy (elective target dose, 45 Gy in 25-30 fractions; tumor target dose, 50-60 Gy in 25-30 fractions). PDR-BT was applied with a tandem-ring applicator. Additional ring-guided titanium needles were used in 4 patients and a multichannel vaginal cylinder in 2 patients. Dose planning was done using 1.5 Tesla T(1)-weighted and T(2)-weighted paratransversal magnetic resonance imaging scans. T(1)-weighted visible oil-containing tubes were used for applicator reconstruction. The prescribed standard dose for PDR-BT was 10 Gy (1 Gy/pulse, 1 pulse/h) for two to three fractions to reach a physical dose of 80 Gy to Point A. The total dose (external beam radiotherapy plus brachytherapy) was normalized to an equivalent dose in 2-Gy fractions using alpha/beta = 10 Gy for tumor, alpha/beta = 3 Gy for normal tissue, and a repair half-time of 1.5 h. The goal of optimization was dose received by 90% of the target volume (D(90)) of > or =85 Gy(alpha/beta10) in the high-risk clinical target volume (cervix and remaining tumor at brachytherapy), but keeping the minimal dose to 2 cm(3) of the bladder and rectum/sigmoid at <90 and <75 Gy(alpha/beta3), respectively.
Using three-dimensional optimization, all dose-volume histogram constraints were met in 16 of 21 patients compared with 3 of 21 patients with two-dimensional library plans (p < 0.001). Optimization increased the minimal target dose (D(100)) of the high-risk clinical target volume (p < 0.007) and decreased the minimal dose to 2 cm(3) for the sigmoid significantly (p = 0.03). For the high-risk clinical target volume, D(90) was 91 +/- 8 Gy(alpha/beta10) and D(100) was 76 +/- 5 Gy(alpha/beta10). The minimal dose to 2 cm(3) for the bladder, rectum, and sigmoid was 73 +/- 6, 67 +/- 6, and 69 +/- 6 Gy(alpha/beta3), respectively.
The results of our study have shown that magnetic resonance imaging-guided optimization of PDR-BT for locally advanced cervical cancer significantly improved the dose-volume histogram parameters.
To determine current practice patterns with regard to gynecologic high-dose-rate (HDR) brachytherapy among international members of the Gynecologic Cancer Intergroup (GCIG) in Japan/Korea (Asia), ...Australia/New Zealand (ANZ), Europe (E), and North America (NAm).
A 32-item survey was developed requesting information on brachytherapy practice patterns and standard management for Stage IB-IVA cervical cancer. The chair of each GCIG member cooperative group selected radiation oncology members to receive the survey.
A total of 72 responses were analyzed; 61 respondents (85%) used HDR. The three most common HDR brachytherapy fractionation regimens for Stage IB-IIA patients were 6 Gy for five fractions (18%), 6 Gy for four fractions (15%), and 7 Gy for three fractions (11%); for Stage IIB-IVA patients they were 6 Gy for five fractions (19%), 7 Gy for four fractions (8%), and 7 Gy for three fractions (8%). Overall, the mean combined external-beam and brachytherapy equivalent dose (EQD2) was 81.1 (standard deviation SD 10.16). The mean EQD2 recommended for Stage IB-IIA patients was 78.9 Gy (SD 10.7) and for Stage IIB-IVA was 83.3 Gy (SD 11.2) (p = 0.02). By region, the mean combined EQD2 was as follows: Asia, 71.2 Gy (SD 12.65); ANZ, 81.18 (SD 4.96); E, 83.24 (SD 10.75); and NAm, 81.66 (SD, 6.05; p = 0.02 for Asia vs. other regions).The ratio of brachytherapy to total prescribed dose was significantly higher for Japan (p = 0.0002).
Although fractionation patterns may vary, the overall mean doses administered for cervical cancer are similar in Australia/New Zealand, Europe, and North America, with practitioners in Japan administering a significantly lower external-beam dose but higher brachytherapy dose to the cervix. Given common goals, standardization should be possible in future clinical trials.
Brachytherapy in the treatment of locally advanced cervical cancer has changed substantially because of the introduction of combined intracavitary/interstitial applicators and an adaptive target ...concept, which is the focus of the prospective, multi-institutional EMBRACE study (www.embracestudy.dk) on image-guided adaptive brachytherapy (IGABT). So far, little has been reported about the development of early to late vaginal morbidity in the frame of IGABT. Therefore, the aim of the present EMBRACE analysis was to evaluate the manifestation pattern of vaginal morbidity during the first 2 years of follow-up.
In total, 588 patients with a median follow-up time of 15 months and information on vaginal morbidity were included. Morbidity was prospectively assessed at baseline, every 3 months during the first year, and every 6 months in the second year according to the Common Terminology Criteria for Adverse Events, version 3, regarding vaginal stenosis, dryness, mucositis, bleeding, fistula, and other symptoms. Crude incidence rates, actuarial probabilities, and prevalence rates were analyzed.
At 2 years, the actuarial probability of severe vaginal morbidity (grade ≥3) was 3.6%. However, mild and moderate vaginal symptoms were still pronounced (grade ≥1, 89%; grade ≥2, 29%), of which the majority developed within 6 months. Stenosis was most frequently observed, followed by vaginal dryness. Vaginal bleeding and mucositis were mainly mild and infrequently reported.
Severe vaginal morbidity within the first 2 years after definitive radiation (chemo)therapy including IGABT with intracavitary/interstitial techniques for locally advanced cervical cancer is limited and is significantly less than has been reported from earlier studies. Thus, the new adaptive target concept seems to be a safe treatment with regard to the vagina being an organ at risk. However, mild to moderate vaginal morbidity is still pronounced with currently applied IGABT, and it needs further attention.
Abstract 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 ± 14 Gy to 92 ± 13 Gy ( 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 ⩾ 30 cm3 was 10% higher ( p = 0.02) in the IC/IS group. No difference was found for CTVHR < 30 cm3 ( 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.
Abstract 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 ( D 0.1 cm 3 , D 2 cm 3 ), 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 25.4 months. 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 , D 0.1 cm 3 , and D 2 cm 3 were respectively: 66.2 ± 9.1 Gy, 72.9 ± 11.9 Gy, and 62.8 ± 7.6 Gy. 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 D 2 cm 3 , D 0.1 cm 3 , and DICRU and the probability of grade 1–4, 2–4, and 3–4 rectal events. The equieffective D 2 cm 3 for a 10% probability for overall rectal grade ⩾ 2 morbidity was 69.5 Gy ( p < 0.0001). After sorting patients according to 6 D 2 cm 3 levels, less favorable outcome was observed in the high dose subgroups, for bleeding, proctitis, fistula, and overall rectal morbidity. A D 2 cm 3 ⩾ 75 Gy was associated with a 12.5% risk of fistula at 3 years versus 0–2.7% for lower doses ( p > 0.001). A D 2 cm 3 < 65 Gy was associated with a two times lower risk of proctitis than D 2 cm 3 ⩾ 65 Gy. Conclusions Significant correlations were established between late rectal morbidity, overall and single endpoints, and dose–volume ( D 2 cm 3 , D 0.1 cm 3 ) and dose-point (DICRU ) parameters. A D 2 cm 3 ⩽ 65 Gy is associated with more minor and less frequent rectal morbidity, whereas a D 2 cm 3 ⩾ 75 Gy is associated with more major and more frequent rectal morbidity.
To describe the evolution of external beam radiation therapy (EBRT) from EMBRACE-I (general guidelines for EBRT) to the initial phase of the EMBRACE-II study (detailed protocol for EBRT).
EMBRACE-I ...enrolled 1416 locally advanced cervical cancer patients treated with chemoradiation including image-guided adaptive brachytherapy during 2008 to 2015. From March 2016 until March 2018, 153 patients were enrolled in the ongoing EMBRACE-II study, which involves a comprehensive detailed strategy and accreditation procedure for EBRT target contouring, treatment planning, and image guidance. EBRT planning target volumes (PTVs), treated volumes (V43 Gy), and conformity index (CI; V43 Gy/PTV) were evaluated in both studies and compared.
For EMBRACE-I, conformal radiation therapy (60% of patients) or intensity-modulated radiation therapy (IMRT) and volumetric arc therapy (VMAT; 40%) was applied with 45 to 50 Gy over 25 to 30 fractions to the elective clinical target volume (CTV). For pelvic CTVs (82%), median PTV and V43 Gy volumes were 1549 and 2390 mL, respectively, and CI was 1.54. For pelvic plus paraortic nodal (PAN) CTVs (15%), median PTV and V43 Gy volumes were 1921 and 2895 mL, and CI was 1.51. For pelvic CTVs treated with 45 to 46 Gy, the use of conformal radiation therapy was associated with a median V43 Gy volume that was 546 mL larger than with IMRT/VMAT. For pelvic CTVs treated with IMRT, the use of a dose prescription ≥48 Gy was associated with a median V43 Gy volumes that was 428 mL larger than with a dose prescription of 45 to 46 Gy. For EMBRACE-II, all patients were treated with: IMRT/VMAT, daily IGRT, 45 Gy over 25 fractions for the elective CTV, and simultaneously integrated boost for pathologic lymph nodes. For pelvic CTVs (61%), median PTV and V43 Gy volumes were 1388 and 1418 mL, and CI was 1.02. For pelvic plus PAN CTVs (32%), median PTV and V43 Gy volumes were 1720 and 1765 mL, and CI was 1.03. From EMBRACE-I to initial II, median V43 Gy was decreased by 972 mL (41%) and 1130 mL (39%), and median CI decreased from 1.54 to 1.02 and 1.51 to 1.03 for pelvic and pelvic plus PAN irradiation, respectively.
Application of IMRT/VMAT, IGRT, and a 45-Gy dose provides the potential of higher conformality inducing significant reduction of treated volume. Adherence to a detailed protocol including comprehensive accreditation, as in EMBRACE-II, reduces considerably V43 Gy and V50 Gy and improves conformality and interinstitutional consistency.
•Doses to the vaginal dose points predicts well the risk of vaginal morbidity.•Higher doses to the vaginal PIBS points are associated with vaginal stenosis.•A shorter vaginal reference length is ...associated with ≥grade 2 vaginal stenosis.
To evaluate dose–effect relationships between vaginal dose points and vaginal stenosis in patients treated for locally advanced cervical cancer with radio(chemo)therapy and image-guided adaptive brachytherapy.
Patients from six centres participating in the EMBRACE-I study were included. Information on doses to different vaginal dose points, including the Posterior-Inferior Border of Symphysis (PIBS) points and recto-vaginal reference (RV-RP) point, were retrieved from the treatment planning system. In addition, the vaginal reference length (VRL) was evaluated. Vaginal stenosis was prospectively assessed according to the CTCAEv3.0 system at baseline and follow-up. Primary endpoint was grade 2 or higher (G ≥ 2) vaginal stenosis. Impact of dose to the vaginal dose points, and impact of VRL, age, vaginal involvement and applicator on vaginal stenosis G ≥ 2 was evaluated with a Cox proportional-hazard regression model.
301 patients were included. Median follow-up was 49 months. During follow-up, the incidence of G0, G1, G2, and G3 vaginal stenosis was 25% (76), 52% (158), 20% (59) and 3% (8), respectively. Median total doses to PIBS+2 cm, PIBS, PIBS-2 cm and the RV-RP were 52.9 (IQR 49.3–64.7), 41.0 (IQR 15.4–49.0), 4.1 (IQR 2.9–7.0) and 64.6 (IQR 60.0–70.6) Gy EQD23, respectively. Higher doses to the PIBS, PIBS + 2 cm and RV-RP points were significantly associated with increased risk for vaginal stenosis G ≥ 2. Other risk factors for vaginal stenosis were: vaginal involvement at diagnosis, higher age, shorter VRL and use of a tandem-ovoid applicator.
Higher doses to the PIBS+2 cm, PIBS and RV-RP dose points are associated with vaginal stenosis G ≥ 2.
Abstract 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 70–80 Gy EQD2. Conclusion TCP is robust to dosimetric uncertainties when dose prescription is in the more flat region of the dose–response curve at doses >75 Gy. For OARs, improved clinical outcome is expected by reduction of uncertainties via sophisticated dose delivery and treatment verification.
Abstract Background/purpose To identify risk factors for vaginal stenosis and to establish a dose–effect relationship for image-guided brachytherapy in locally advanced cervical cancer. ...Materials/Methods Patients from the ongoing EMBRACE study with prospectively assessed morbidity (CTCAEv3.0) at baseline and at least one follow-up were selected. Patient-, disease- and treatment characteristics were tested as risk factors for vaginal stenosis G ⩾ 2 in univariate and multivariable analyses (Cox proportional hazards model) and a dose–effect curve was deduced from the estimates. The ICRU rectum point was used to derive the recto-vaginal reference point dose. Results In 630 patients included (median follow-up 24 months), 2-year actuarial estimate for vaginal stenosis G ⩾ 2 was 21%. Recto-vaginal reference point dose (HR = 1.025, p = 0.029), external beam radiotherapy (EBRT) dose >45 Gy/25 fractions (HR = 1.770, p = 0.056) and tumor extension in the vagina (HR = 2.259, p ⩽ 0.001) were risk factors for vaginal stenosis, adjusted for center reporting effects. Based on the model curve, the risk was 20% at 65 Gy, 27% at 75 Gy and 34% at 85 Gy (recto-vaginal reference point dose). Conclusion Keeping the EBRT dose at 45 Gy/25 fractions and decreasing the dose contribution of brachytherapy to the vagina decrease the risk of stenosis. A planning aim of ⩽65 Gy EQD2 (EBRT + brachytherapy dose) to the recto-vaginal reference point is therefore proposed.
To report clinical and treatment characteristics, remission and failure patterns, and risk factors for local failure (LF) from the EMBRACE-I study.
EMBRACE-I was a prospective, observational, ...multicenter cohort study on magnetic resonance imaging-based image-guided adaptive brachytherapy (MR-IGABT) in locally advanced cervical cancer. Treatment consisted of external beam radiotherapy, concurrent chemotherapy, and MR-IGABT. LF was defined as progressive or recurrent disease in the cervix, uterus, parametria, pelvic wall, or vagina. Competing risk analysis was used to estimate local tumor control (LC) and Cox proportional regression models for multivariable analysis and dose-response analysis.
One thousand three hundred eighteen patients with a median follow-up of 52 months were available for this analysis. Eighty-one patients had persistent disease 3 months after end of treatment. Of those, 60 patients achieved LC at 6-9 months without further treatment, whereas 21 patients had progressive disease. In addition, 77 patients developed a local recurrence after complete remission comprising a total number of 98 LFs. LFs were located inside the MR-IGABT target volumes in 90% of patients with LF. In multivariable analysis, histology, minimal dose to 90% of high-risk clinical target volume (CTV
), maximum tumor dimension, CTV
> 45 cm
, overall treatment time, tumor necrosis on magnetic resonance imaging at diagnosis, uterine corpus infiltration at diagnosis and at MR-IGABT, and mesorectal infiltration at MR-IGABT had significant impact on LF. Dose-response analysis showed that a minimal dose to 90% of 85 Gy to the CTV
led to 95% (95% CI, 94 to 97) LC 3 years postintervention for squamous cell in comparison to 86% (95% CI, 81 to 90) for adeno/adenosquamous carcinoma histology.
The present study demonstrates the safety and validity of the GYN GEC-ESTRO/ICRU-89 target concept and provides large-scale evidence for dose prescription and new risk factors for LF in MR-IGABT in locally advanced cervical cancer.
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