Abstract 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 3/5 years 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 43 months, 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 ± 2.5 Gy; 77.4% received concurrent chemotherapy. Mean D90 HRCTV was 87 ± 15 Gy (EQD210 ), mean D2cc was: bladder 81 ± 22 Gy, rectum 64 ± 9 Gy, sigmoid 66 ± 10 Gy and bowel 64 ± 9 Gy (all EQD23 ). The 3/5-year actuarial LC, PC, CSS, OS were 91%/89%, 87%/84%, 79%/73%, 74%/65%. Actuarial LC at 3/5 years for IB, IIB, IIIB was 98%/98%, 93%/91%, 79%/75%. Actuarial PC at 3/5 years 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.
Purpose
To investigate the dose modulation capability of a novel MRI‐compatible direction modulated brachytherapy (DMBT) tandem applicator design with various high‐density shielding materials for ...brachytherapy treatment of cervical cancer. The shield materials that have been evaluated are tantalum (Ta), pure tungsten (W), gold (Au), rhenium (Re), osmium (Os), platinum (Pt), iridium (Ir), and W′ tungsten alloy (95%W, 3.5%Ni, 1.5%Cu).
Materials and methods
The recently proposed six‐channel DMBT tandem is composed of nonmagnetic tungsten alloy (W′) rod with diameter of 5.4 mm and coated with 0.3‐mm thick bio‐safe plastic sheath. The tandem shielding material can, however, be individually replaced with various other shields to create directional radiation. Monte Carlo N‐Particle (MCNP) code was used to calculate the three‐dimensional (3D) dose distributions in a water phantom for an HDR 192Ir (mHDR‐v2) source inside each DMBT tandem with various shields and a plastic conventional tandem (Con.T). Then, the 3D dose distributions were imported into an in‐house‐coded inverse planning optimization algorithm to obtain optimal plans for 12 clinical cases chosen at random from the international RetroEMBRACE dataset involving conventional tandem and ring (Con.T&R) applicators. All plans generated by the DMBT tandem and ring (DMBT&R) with the tungsten alloy DMBT(W′)&R were compared with the corresponding Con.T&R plans, to generate benchmark results. These benchmark results were then considered as reference plans for other shields performances. Plans were normalized to receive the same high‐risk clinical target volume (CTVHR) D90. The D100, D10, and V100 for CTVHR, and D2cm3 for organs at risk (OARs) of bladder, sigmoid, and rectum were calculated and compared.
Results
Transmission factor (TF), that is, the dose in the backside of the DMBT shield over that in the front opening, at a 5 cm distance, were 36.6%, 34.8%, 31.9%, 28.9%, 27.9%, 26.2%, 26.2%, and 25.5%, for Ta, W′, W, Re, Au, Os, Pt, and Ir shields, respectively. On average, the CTVHR values for D100, V100, D10 were not significantly different across all DMBT&R shields and the Con.T&R plans (P > 0.219). For the D2cm3, the benchmark results showed significant reductions (P < 0.03), that is, on average, −8.3% for bladder, −10.7% for rectum, and −10.1% for sigmoid, compared to the Con.T&R plans. However, the various shields showed little improvement from the tungsten alloy (W′), where on average, rectum (bladder) sigmoid D2cm3 were reduced by −1.32% (−0.85%) −1.01%, −1.25% (−0.78%) −0.91%, −1.22% (−0.75%) −0.86%, −0.94% (−0.60%) −0.70%, −0.84% (−0.51%) −0.59%, and −0.38% (−0.24%) −0.23% for Ir, Pt, Os, Au, Re, and W shields, relative to the benchmark W′ DMBT plans, respectively. These corresponding values for Ta increased by +0.28% (+0.08%) +0.25%, respectively.
Conclusion
The Ir, Pt, Os, Au, Re, and W shielding materials, respectively, in descending order, lead to better OAR sparing than the DMBT(W′)&R plans. However, the amount of improvement is limited and clinically insignificant. This finding suggests that the initial W′ shield remains a suitable choice given the proven MR compatibility, for use in MR‐guided adaptive brachytherapy of cervical cancer.
Globally, cervical cancer has the fourth highest cancer incidence and mortality in women. Cervical cancer is unique because it has effective prevention, screening, and treatment options. This review ...discusses the current cervical cancer advances with a focus on locally advanced cervical cancer. Topics discussed include diagnostic imaging principles, surgical management with adjuvant therapy and definitive concurrent chemoradiotherapy. Emphasis is given on current advances and future research directions in radiation therapy (RT) with an emphasis on three-dimensional brachytherapy, intensity-modulated RT, image-guided RT, proton RT and hyperthermia.
Abstract 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 46 months, 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 ⩾85 Gy (D90) delivered in 7 weeks provides 3-year local control rates of >94% in limited size CTVHR (20 cm3 ), >93% in intermediate size (30 cm3 ) and >86% in large size (70 cm3 ) CTVHR . CTVIR and GTVres dose of ⩾60 Gy and ⩾95 Gy (D98) leads to similar local control. A dose of 5 Gy (CTVHR ) is required to compensate an increase of OTT by one week. Increased CTVHR volume by 10 cm3 requires additional 5 Gy for equivalent local control.
•Significant local control improvement in cervical cancer patients due to hyperthermia was validated in a recent patient cohort.•Hyperthermia is effective in combination with modern radiotherapy ...techniques, such as image guided brachytherapy.
Addition of deep hyperthermia results in improved local control (LC) and overall survival (OS) compared to radiotherapy alone in patients with cervical carcinoma. Previously, we showed that the thermal dose of hyperthermia significantly correlates with LC and disease specific survival (DSS). Over the last decade, new radiation techniques were introduced resulting in improved LC.
To validate the effect of thermal dose in a more recent cohort of patients treated with modern radiotherapy techniques, including image guided brachytherapy (IGBT).
We analyzed primary cervical carcinoma patients treated with a combination of radiotherapy and deep hyperthermia between 2005 and 2016 at our institute. Data on patient, tumor and treatment were collected including the thermal dose parameters TRISE and CEM43T90. Follow-up data on LC, disease free survival, DSS, OS as well as late toxicity data were collected. Data were analyzed using the Cox proportional hazard and Kaplan–Meier analyses.
227 patients were included. In multivariate analysis, histology, FIGO stage, lymphadenopathy, TRISE, CEM43T90 and IGBT had a significant effect on LC. In the patients treated with IGBT, the thermal dose parameter TRISE remained to have a significant effect on LC in univariate analysis.
The positive association between thermal dose and clinical outcome is replicated in an independent, recent cohort of cervical carcinoma patients. Importantly, in patients receiving IGBT, the effect of thermal dose on clinical outcome is still observed.
Abstract Purpose In 2005 a French multicentric non randomized prospective study was initiated to compare two groups of patients treated for cervix carcinoma according to brachytherapy (BT) method: 2D ...vs 3D dosimetry. The BT dosimetric planning method was chosen for each patient in each center according to the availability of the technique. This study describes the results for 705 out of 801 patients available for analysis. Patients and methods For the 2D arm, dosimetry was planned on orthogonal X-Rays using low dose rate (LDR) or pulsed dose rate (PDR) BT. For the 3D arm, dosimetry was planned on 3D imaging (mainly CT) and performed with PDR BT. Each center could follow the dosimetric method they were used to, according to the chosen radioelement and applicator. Manual or graphical optimization was allowed. Three treatment regimens were defined: Group 1: BT followed by surgery; 165 patients (2D arm: 76; 3D arm: 89); Group 2: EBRT (+chemotherapy), BT, then surgery; 305 patients (2D arm: 142; 3D arm: 163); Group 3: EBRT (+chemotherapy), then BT; 235 patients, (2D arm: 118; 3D arm: 117). The DVH parameters for CTVs (High Risk CTV and Intermediate Risk CTV) and organs at risk (OARs) were computed as recommended by GYN GEC ESTRO guidelines. Total doses were converted to equivalent doses in 2 Gy fractions (EQD2). Side effects were prospectively assessed using the CTCAEv3.0. Results The 2D and 3D arms were well balanced with regard to age, FIGO stage, histology, EBRT dose and chemotherapy. For each treatment regimen, BT doses and volumes were comparable between the 2D and 3D arms in terms of dose to point A, isodose 60 Gy volume, dose to ICRU rectal points, and TRAK. Dosimetric data in the 3D arm showed that the dose delivered to 90% of the High Risk CTV (HR CTV D90) was respectively, 81.2 Gyα/β10 , 63.2 Gyα/β10 and 73.1 Gyα/β10 for groups 1, 2 and 3. The Intermediate Risk (IR) CTV D90 was respectively, 58.5 Gyα/β10 , 57.3 Gyα/β10 and 61.7 Gyα/β10 for groups 1, 2 and 3. For the OARs, doses delivered to D2 cc ranged 60–70 Gyα/β3 for the bladder, 33–61 Gyα/β3 for the rectum, and 44–58 Gyα/β3 for the sigmoid according to the regimen. At 24 months, local relapse-free survival was 91.9% and 100% in group 1, 84.7% and 93% in group 2, 73.9% and 78.5% in group 3; grade 3–4 toxicity rate was 14.6% and 8.9% in group 1, 12.5% and 8.8% in group 2, and 22.7% and 2.6% in group 3 for 2D and 3D arm. Conclusion This multicentric study has shown that 3D BT is feasible and safe in routine practice. It has improved local control with half the toxicity observed with 2D dosimetry. The combined treatment with radiotherapy and surgery was more toxic than definitive radiotherapy. For patients with advanced tumors, it is necessary to improve coverage of target volumes without raising toxicity.
Introduction
Although positron‐emission tomography (PET) plays an integral role in cervix cancer diagnosis, there are limited data on PET‐based image‐guided brachytherapy (IGBT). We aimed to report ...the long‐term outcomes of PET‐based IGBT.
Methods
We reviewed 151 patients treated with definitive radiotherapy (RT), including PET‐based IGBT between 2009 and 2018. After median 45 Gy of external beam RT with the four‐field technique, a median 24 Gy of high‐dose‐rate iridium‐192 IGBT was delivered in six fractions with Fletcher‐Suit tandem and ovoids. All patients underwent 18F‐fluorodeoxyglucose‐PET/computed tomography planning with a brachytherapy applicator. Multivariable analysis of local control (LC) was performed using Cox regression analysis.
Results
The median high‐risk clinical target volume (HRCTV) and HRCTV D90% were 51.8 (interquartile range IQR 35.9–79.4) cm3 and 77.7 (IQR 74.7–81.2) Gy, respectively. With a median follow‐up of 57 (IQR 24.3–81.4) months, the 5‐year LC rate was 89.2%. HRCTV ≥72 cm3 was associated with inferior LC (hazard ratio, 3.72, p = .017) after multivariable analysis: the 5‐year LC rates were 94.0% and 77.9% for HRCTVs ≥72 and < 72 cm3, respectively (p = .002). The impact of HRCTV D90% ≥70 Gy on LC was significant in patients with an HRCTV ≥72 cm3 compared to that in those with HRCTV < 72 cm3. Patients with adeno/adenosquamous carcinoma demonstrated inferior LC in both groups. There were 13 (8.6%) and 11 (7.3%) patients with acute and late severe toxicities after RT.
Conclusion
PET‐based IGBT leads to favorable LC, and HRCTV ≥72 cm3 requires further dose escalation to improve outcomes.
Development of a risk prediction model to reliably identify patients undergoing ALL treatment at a higher risk of life threatening sepsis based on analysis of 2068 fever episodes in 377 patients treated on the consecutive Malaysia‐Singapore ALL clinical trials.
The standard of care for the definitive treatment of locoregionally advanced cervical cancer is external beam radiation therapy (EBRT) with concurrent chemotherapy followed by a brachytherapy boost. ...Historically, EBRT was delivered via a two-dimensional technique based primarily on bony landmarks. This gave way to three-dimensional conformal radiation therapy, which allows for dose calculation and adjustment based on individual tumour and patient anatomy. Further technological advances have established intensity-modulated radiation therapy (IMRT) as a standard treatment modality, given the ability to maintain tumoricidal doses to target volumes while reducing unwanted radiation dose to nearby critical structures, thereby reducing toxicity. Routine image guidance allows for increased confidence in patient alignment prior to treatment, and the ability to visualise the daily position of the targets and organs at risk has been instrumental in allowing safe reductions in treated volumes. Additional EBRT technologies, including proton therapy and stereotactic body radiation therapy, may further improve the therapeutic index. In the realm of brachytherapy, a shift from point-based dose planning to image-guided brachytherapy has been associated with improved local control and reduced toxicity, with additional refinement ongoing. Here we will discuss these advances, the supporting data and future directions.
•Overlap volume histograms can be used for prediction models of D2cm3 values.•Prediction models are robust to interstitial needle use and applicator types.•Prediction models can be used in a ...multi-center setting.•Suboptimal plans can be detected when models are trained on high-quality data.
Image-guided adaptive brachytherapy (IGABT) is a key component in the treatment of cervical cancer, but the nature of the clinical workflow makes it vulnerable to suboptimal plans, as the theoretical optimal plan depends heavily on organ configuration. Patient anatomy-based quality-assurance (QA) with overlap volume histograms (OVHs) is a promising tool to detect such suboptimal plans, and in this analysis its suitability as a multi-institutional clinical QA tool is investigated.
A total of 223 plans of 145 patients treated in accordance with the current state-of-the-art IGABT protocols from UMC Utrecht (UMCU) and Erasmus MC (EMC) were included. Machine-learning models were trained to predict dose D2cm3 to bladder, rectum, sigmoid and small bowel with the help of OVHs. For this strategy, points are sampled on the organs-at-risk (OARs), and the distances of the sampled points to the target are computed and combined in a histogram. Machine-learning models can then be trained to predict dose-volume histograms (DVHs) for unseen data. Single-center model robustness to needle use and applicator type and multi-center model translatability were investigated. Performance of models was assessed by the difference between planned (clinical) and predicted D2cm3 values.
Intra-validation of UMCU data demonstrated OVH model robustness to needle use and applicator type. The model trained on UMCU data was found to be robust within the same protocol on EMC data, for all investigated OARs. Mean squared error between planned and predicted D2cm3 values of OARs ranged between 0.13 and 0.40 Gy within the same protocol, indicating model translatability. For the former protocol cohort of Erasmus MC large deviations were found between the planned and predicted D2cm3 values, indicating plan deviation from protocol. Mean squared error for this cohort ranged from 0.84 to 4.71 Gy.
OVH-based models can provide a solid basis for multi-institutional QA when trained on a sufficiently strict protocol. Further research will quantify the model’s impact as a QA tool.
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.
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