Efficacy and toxicity of chemoradiation with image-guided adaptive brachytherapy for locally advanced cervical cancer.

OBJECTIVE: To evaluate the efficacy and toxicity of primary chemoradiation with image-guided adaptive brachytherapy for locally advanced cervical cancer and to identify predictors of treatment failure and toxicity. METHODS: Retrospective analysis of 155 stage IB-IVA cervical cancer patients treated from 2008 to 2016 with chemoradiation and image-guided adaptive brachytherapy. Treatment consisted of external beam radiotherapy (45 - 48.6 Gy in 1.8 - 2 Gy fractions) with concurrent weekly cisplatin (40 mg/m2, 5 - 6 cycles) and image-guided adaptive brachytherapy (3-4 × 7 Gy high dose rate) using intracavitary or combined intracavitary-interstitial techniques according to GEC-ESTRO (Group Européen de Curiethérapie and the European Society for Radiotherapy and Oncology) recommendations. Incidences of all outcomes were calculated using Kaplan-Meier's methodology. Risk factors for treatment failure and toxicity were identified using Cox's proportional hazards model and the Kruskal-Wallis H-test respectively. RESULTS: Median follow-up was 57 months. Five-year local control was 90.4 %. Five-year para-aortic lymph node metastasis-free and distant metastasis-free survival were 85.3 % and 70.2 % respectively. Tumor size and lymph node metastasis were independent risk factors for treatment failure. Cumulative incidences of severe late bladder, rectal, bowel, and vaginal toxicity were 0.8%, 3.3%, 3.6%, and 1.4% respectively at 5 years of follow-up. Combined intracavitary-interstitial brachytherapy techniques were associated with less vaginal morbidity. CONCLUSIONS: Primary chemoradiation with image-guided adaptive brachytherapy for locally advanced cervical cancer is a highly effective local and loco-regional treatment. However, survival is compromised by the occurrence of distant metastasis. Patients with large tumors and nodal involvement at diagnosis are at increased risk and may benefit from intensified treatment. Severe late gastrointestinal and urogenital toxicity is limited and may be further reduced by increasing conformity, using combined intracavitary-interstitial techniques and lowering doses to organs at risk.

Keeping your best options open with AI-based treatment planning in prostate and cervix brachytherapy.

PURPOSE: Without a clear definition of an optimal treatment plan, no optimization model can be perfect. Therefore, instead of automatically finding a single "optimal" plan, finding multiple, yet different near-optimal plans, can be an insightful approach to support radiation oncologists in finding the plan they are looking for. METHODS AND MATERIALS: BRIGHT is a flexible AI-based optimization method for brachytherapy treatment planning that has already been shown capable of finding high-quality plans that trade-off target volume coverage and healthy tissue sparing. We leverage the flexibility of BRIGHT to find plans with similar dose-volume criteria, yet different dose distributions. We further describe extensions that facilitate fast plan adaptation should planning aims need to be adjusted, and straightforwardly allow incorporating hospital-specific aims besides standard protocols. RESULTS: Results are obtained for prostate (n = 12) and cervix brachytherapy (n = 36). We demonstrate the possible differences in dose distribution for optimized plans with equal dose-volume criteria. We furthermore demonstrate that adding hospital-specific aims enables adhering to hospital-specific practice while still being able to automatically create cervix plans that more often satisfy the EMBRACE-II protocol than clinical practice. Finally, we illustrate the feasibility of fast plan adaptation. CONCLUSIONS: Methods such as BRIGHT enable new ways to construct high-quality treatment plans for brachytherapy while offering new insights by making explicit the options one has. In particular, it becomes possible to present to radiation oncologists a manageable set of alternative plans that, from an optimization perspective are equally good, yet differ in terms of coverage-sparing trade-offs and shape of the dose distribution.

A new concept for non-invasive renal tumour ablation using real-time MRI-guided radiation therapy.

OBJECTIVE To present a new concept for non-invasive renal tumour ablation using real-time magnetic resonance imaging (MRI)-guided radiation therapy. All currently available treatment techniques for localized renal cell carcinoma (RCC) have to be performed in a laparoscopic or percutaneous way. MATERIALS AND METHODS A technical prototype MRI-accelerator which performs real-time 1.5 T MRI imaging during the irradiation has been constructed. We performed a technical feasibility study on real-time MRI-guided arc therapy using repeated breath-holds for renal tumour ablation by (i) investigating renal mobility during breath-holding, (ii) performing dose calculation and (iii) measuring the radiation delivery time on a phantom. The renal mobility during free breathing and end-expiration breath-holding during 15 s was investigated for three patients with renal tumour appearance. Conventional MRI screening data of four patients was used for arc therapy dose calculation. Tumour and normal tissues were delineated and a tumour margin of 3 mm was applied. The radiation delivery time of a 25-Gy arc therapy plan was measured on a phantom. RESULTS Renal mobility during free breathing varied from 10 to 25 mm, whereas breath-holding resulted in nearly non-moving kidneys (0 to 2 mm) for all patients. Arc therapy dose calculation resulted in an adequate tumour coverage. The radiation delivery time of the arc therapy plan was about 10 min. This means that 20 to 40 repeated breath-holds of 15 to 30 s will be needed for a single session treatment. A higher maximum dose rate would reduce the number of breath-holds needed and improve patient comfort. A phase I study will be started to proof the clinical feasibility. CONCLUSION Real-time MRI-guided radiation therapy using an MRI-accelerator might become a valuable non-invasive alternative to the current RCC treatment options.

PROTECT: Prospective Phase-II-Trial Evaluating Adaptive Proton Therapy for Cervical Cancer to Reduce the Impact on Morbidity and the Immune System.

External beam radiation therapy (EBRT) with concurrent chemotherapy followed by brachytherapy is a very effective treatment for locally advanced cervical cancer (LACC). However, treatment-related toxicity is common and reduces the patient's quality of life (QoL) and ability to complete treatment or undergo adjuvant therapies. Intensity modulated proton therapy (IMPT) enables a significant dose reduction in organs at risk (OAR), when compared to that of standard intensity-modulated radiation therapy (IMRT) or volumetric-modulated arc therapy (VMAT). However, clinical studies evaluating whether IMPT consequently reduces side effects for LACC are lacking. The PROTECT trial is a nonrandomized prospective multicenter phase-II-trial comparing clinical outcomes after IMPT or IMRT/VMAT in LACC. Thirty women aged >18 years with a histological diagnosis of LACC will be included in either the IMPT or IMRT/VMAT group. Treatment includes EBRT (45 Gy in 25 fractions of 1.8 Gy), concurrent five weekly cisplatin (40 mg/m2), and 3D image (MRI)-guided adaptive brachytherapy. The primary endpoint is pelvic bones Dmean and mean bowel V15Gy. Secondary endpoints include dosimetric parameters, oncological outcomes, health-related QoL, immune response, safety, and tolerability. This study provides the first data on the potential of IMPT to reduce OAR dose in clinical practice and improve toxicity and QoL for patients with LACC.

Applicator visualization using ultrashort echo time MRI for high-dose-rate endorectal brachytherapy.

PURPOSE: The individual channels in an endorectal applicator for high-dose-rate endorectal brachytherapy are not visible on standard MRI sequences. The aim of this study was to test whether an ultrashort echo time (UTE) MRI sequence could be used to visualize the individual channels to enable MR-only treatment planning for rectal cancer. METHODS AND MATERIALS: We used a radial three-dimensional (3D) UTE pulse sequence and acquired images of phantoms and two patients with rectal cancer. We rigidly registered a UTE image and CT scan of an applicator phantom, based on the outline of the applicator. One observer compared channel positions on the UTE image and CT scan in five slices spaced 25 mm apart. To quantify geometric distortions, we scanned a commercial 3D geometric quality assurance phantom and calculated the difference between detected marker positions on the UTE image and corresponding marker positions on two 3D T1-weighted images with opposing readout directions. RESULTS: On the UTE images, there is sufficient contrast to discern the individual channels. The difference in channel positions on the UTE image compared with the CT was on average -0.1 ± 0.1 mm (left-right) and 0.1 ± 0.3 mm (anteroposterior). After rigid registration to the 3D T1-weighted sequences, the residual 95th percentile of the geometric distortion inside a 550-mm-diameter sphere was 1.0 mm (left-right), 0.9 mm (anteroposterior), and 0.9 mm (craniocaudal). CONCLUSIONS: With a UTE sequence, the endorectal applicator and individual channels can be adequately visualized in both phantom and patients. The geometrical fidelity is within an acceptable range.

Radiotherapy quality assurance for mesorectum treatment planning within the multi-center phase II STAR-TReC trial: Dutch results.

BACKGROUND: The STAR-TReC trial is an international multi-center, randomized, phase II study assessing the feasibility of short-course radiotherapy or long-course chemoradiotherapy as an alternative to total mesorectal excision surgery. A new target volume is used for both (chemo)radiotherapy arms which includes only the mesorectum. The treatment planning QA revealed substantial variation in dose to organs at risk (OAR) between centers. Therefore, the aim of this study was to determine the treatment plan variability in terms of dose to OAR and assess the effect of a national study group meeting on the quality and variability of treatment plans for mesorectum-only planning for rectal cancer. METHODS: Eight centers produced 25 × 2 Gy treatment plans for five cases. The OAR were the bowel cavity, bladder and femoral heads. A study group meeting for the participating centers was organized to discuss the planning results. At the meeting, the values of the treatment plan DVH parameters were distributed among centers so that results could be compared. Subsequently, the centers were invited to perform replanning if they considered this to be necessary. RESULTS: All treatment plans, both initial planning and replanning, fulfilled the target constraints. Dose to OAR varied considerably for the initial planning, especially for dose levels below 20 Gy, indicating that there was room for trade-offs between the defined OAR. Five centers performed replanning for all cases. One center did not perform replanning at all and two centers performed replanning on two and three cases, respectively. On average, replanning reduced the bowel cavity V20Gy by 12.6%, bowel cavity V10Gy by 22.0%, bladder V35Gy by 14.7% and bladder V10Gy by 10.8%. In 26/30 replanned cases the V10Gy of both the bowel cavity and bladder was lower, indicating an overall lower dose to these OAR instead of a different trade-off. In addition, the bowel cavity V10Gy and V20Gy showed more similarity between centers. CONCLUSIONS: Dose to OAR varied considerably between centers, especially for dose levels below 20 Gy. The study group meeting and the distribution of the initial planning results among centers resulted in lower dose to the defined OAR and reduced variability between centers after replanning. TRIAL REGISTRATION: The STAR-TReC trial, ClinicalTrials.gov Identifier: NCT02945566. Registered 26 October 2016, https://clinicaltrials.gov/ct2/show/NCT02945566).

Predictive factors for response and toxicity after brachytherapy for rectal cancer; results from the HERBERT study.

PURPOSE: The HERBERT study was a dose-finding feasibility study of a high-dose rate endorectal brachytherapy (HDREBT) boost after external beam radiotherapy (EBRT) in elderly patients with rectal cancer who were unfit for surgery. This analysis evaluates the association of patient, tumor and dosimetric parameters with tumor response and toxicity after HDREBT in definitive radiotherapy for rectal cancer. PATIENTS AND METHODS: The HERBERT study included 38 inoperable patients with T2-3N0-1 rectal cancer. Thirteen fractions of 3 Gy EBRT were followed by three weekly HDREBT applications of 5-8 Gy per fraction. Clinical and dosimetric parameters were tested for correlation with clinical complete response (cCR), sustained partial/complete response (SR), patient reported bowel symptoms, physician reported acute and late proctitis (CTCAE v3) and endoscopically scored toxicity. RESULTS: Thirty-five patients completed treatment and were included in the current analyses. Twenty of 33 evaluable patients achieved a cCR, the median duration of a sustained response was 32 months. Tumor volume at diagnosis showed a strong association with clinical complete response (OR 1.15; p = 0.005). No dose-response correlation was observed in this cohort. Prescribed dose to the brachytherapy CTV (D90) correlated with acute and late physician reported proctitis while CTV volume, CTV width and high dose regions in the CTV (D1cc/D2cc) were associated with endoscopic toxicity at the tumor site. CONCLUSION: Tumor volume is the most important predictive factor for tumor response and a higher dose to the brachytherapy CTV increases the risk of severe clinically and endoscopically observed proctitis after definitive radiotherapy in elderly patients with rectal cancer.

Robust dose planning objectives for mesorectal radiotherapy of early stage rectal cancer - A multicentre dose planning study.

BACKGROUND AND PURPOSE: Organ preservation strategies are increasingly being explored for early rectal cancer. This requires revision of target volumes according to disease stage, as well as new guidelines for treatment planning. We conducted an international, multicentre dose planning study to develop robust planning objectives for modern radiotherapy of a novel mesorectal-only target volume, as implemented in the STAR-TReC trial (NCT02945566). MATERIALS AND METHODS: The published literature was used to establish relevant dose levels for organ at risk (OAR) plan optimisation. Ten representative patients with early rectal cancer were identified. Treatment scans had mesorectal target volumes as well as bowel cavity, bladder and femoral heads outlined, and were circulated amongst the three participating institutions. Each institution produced plans for short course (SCRT, 5 × 5 Gy) and long course (LCRT, 25 × 2 Gy) treatment, using volumetric modulated arc therapy on different dose planning systems. Optimisation objectives for OARs were established by determining dose metric objectives achievable for ≥90% of plans. RESULTS: Sixty plans, all fulfilling target coverage criteria, were produced. The planning results and literature review suggested optimisation objectives for SCRT: V 10Gy < 180 cm3, V 18Gy < 110 cm3, V 23Gy < 85 cm3 for bowel cavity; V 21Gy < 15% and V 25Gy < 5% for bladder; and V 12.5Gy < 11% for femoral heads. Corresponding objectives for LCRT: V 20Gy < 180 cm3, V 30Gy < 130 cm3, V 45Gy < 90 cm3 for bowel cavity; V 35Gy < 22% and V 50Gy < 7% for bladder; and V 25Gy < 15% for femoral heads. Constraints were validated across all three institutions. CONCLUSION: We utilized a multicentre planning study approach to develop robust planning objectives for mesorectal radiotherapy for early rectal cancer.

Feasibility of Gold Fiducial Markers as a Surrogate for Gross Tumor Volume Position in Image-Guided Radiation Therapy of Rectal Cancer.

PURPOSE: To evaluate the feasibility of fiducial markers as a surrogate for gross tumor volume (GTV) position in image-guided radiation therapy of rectal cancer. METHODS AND MATERIALS: We analyzed 35 fiducials in 19 patients with rectal cancer who received short-course radiation therapy or long-course chemoradiation therapy. Magnetic resonance imaging examinations were performed before and after the first week of radiation therapy, and daily pre- and postirradiation cone beam computed tomography scans were acquired in the first week of radiation therapy. Between the 2 magnetic resonance imaging examinations, the fiducial displacement relative to the center of gravity of the GTV (COGGTV) and the COGGTV displacement relative to bony anatomy were determined. Using the cone beam computed tomography scans, inter- and intrafraction fiducial displacement relative to bony anatomy were determined. RESULTS: The systematic error of the fiducial displacement relative to the COGGTV was 2.8, 2.4, and 4.2 mm in the left-right, anterior-posterior (AP), and craniocaudal (CC) directions, respectively. Large interfraction systematic errors of up to 8.0 mm and random errors up to 4.7 mm were found for COGGTV and fiducial displacements relative to bony anatomy, mostly in the AP and CC directions. For tumors located in the mid and upper rectum, these errors were up to 9.4 mm (systematic) and 5.6 mm (random) compared with 4.9 mm and 2.9 mm for tumors in the lower rectum. Systematic and random errors of the intrafraction fiducial displacement relative to bony anatomy were ≤2.1 mm in all directions. CONCLUSIONS: Large interfraction errors of the COGGTV and the fiducials relative to bony anatomy were found. Therefore, despite the observed fiducial displacement relative to the COGGTV, the use of fiducials as a surrogate for GTV position reduces the required margins in the AP and CC directions for a GTV boost using image-guided radiation therapy of rectal cancer. This reduction in margin may be larger in patients with tumors located in the mid and upper rectum compared with the lower rectum.

EUS-guided fiducial marker placement for radiotherapy in rectal cancer: feasibility of two placement strategies and four fiducial types.

Background and study aims To facilitate image guidance during radiotherapy of rectal cancer, we investigated the feasibility of fiducial marker placement. This study aimed to evaluate technical success rate and safety of two endoscopic ultrasound (EUS)-guided placement strategies and four fiducial types for rectal cancer patients. Patients and methods This prospective multicenter study included 20 participants who were scheduled to undergo rectal cancer treatment with neoadjuvant short-course radiotherapy or chemoradiation. EUS-guided endoscopy was used for fiducial placement at the tumor site (n = 10) or in the mesorectal fat and in the tumor (n = 10). Four fiducial types were used (Visicoil 0.75 mm, Visicoil 0.50 mm, Cook, Gold Anchor). The endpoints were technical success rate and retention of fiducials, the latter of which was evaluated on cone-beam computed tomography scans during the first five radiotherapy fractions. Results A total of 64 fiducials were placed in 20 patients. For each fiducial type, at least three fiducials were successfully placed in all patients. Technical failure consisted of fiducial blockage within the needle (n = 2) and ejection of two preloaded fiducials at once (n = 4). No serious adverse events were reported. In three patients, one of the fiducials was misplaced without clinical consequences; two in the prostate and one in the intraperitoneal cavity. After a median time of 17 days after placement (range 7 - 47 days), a total of 42/64 (66 %) fiducials were still present (24/44 intratumoral vs. 18/20 mesorectal fiducials, P  = 0.009). Conclusions Placement of fiducials in rectal cancer patients is feasible, however, retention rates for intratumoral fiducials were lower (55 %) than for mesorectal fiducials (90 %).

MRI visibility of gold fiducial markers for image-guided radiotherapy of rectal cancer.

BACKGROUND AND PURPOSE: A GTV boost is suggested to result in higher complete response rates in rectal cancer patients, which is attractive for organ preservation. Fiducials may offer GTV position verification on (CB)CT, if the fiducial-GTV spatial relationship can be accurately defined on MRI. The study aim was to evaluate the MRI visibility of fiducials inserted in the rectum. MATERIALS AND METHODS: We tested four fiducial types (two Visicoil types, Cook and Gold Anchor), inserted in five patients each. Four observers identified fiducial locations on two MRI exams per patient in two scenarios: without (scenario A) and with (scenario B) (CB)CT available. A fiducial was defined to be consistently identified if 3 out of 4 observers labeled that fiducial at the same position on MRI. Fiducial visibility was scored on an axial and sagittal T2-TSE sequence and a T1 3D GRE sequence. RESULTS: Fiducial identification was poor in scenario A for all fiducial types. The Visicoil 0.75 and Gold Anchor were the most consistently identified fiducials in scenario B with 7 out of 9 and 8 out of 11 consistently identified fiducials in the first MRI exam and 2 out of 7 and 5 out of 10 in the second MRI exam, respectively. The consistently identified Visicoil 0.75 and Gold Anchor fiducials were best visible on the T1 3D GRE sequence. CONCLUSION: The Visicoil 0.75 and Gold Anchor fiducials were the most visible fiducials on MRI as they were most consistently identified. The use of a registered (CB)CT and a T1 3D GRE MRI sequence is recommended.

Online MRI guidance for healthy tissue sparing in patients with cervical cancer: an IMRT planning study.

BACKGROUND AND PURPOSE: During cervical cancer treatment, target volumes change position and shape due to organ motion and tumour regression. An MRI-accelerator will provide information on these changes by online magnetic resonance imaging (MRI) guidance throughout each treatment fraction. The purpose of this intensity-modulated radiation therapy (IMRT) planning study is to assess the benefit of online MRI guidance in healthy tissue sparing. MATERIALS AND METHODS: Weekly MRI scans of 11 cervical cancer patients were used. We created four IMRT plans per patient, based on these weekly MRI scans, to simulate an online-IMRT approach. We applied a primary and nodal planning target volume (PTV) margin of 4 mm. As reference, we created an IMRT plan based on the pre-treatment MRI scan (pre-IMRT) using a primary and nodal PTV margin of 15 and 10 mm. The weekly defined bladder, rectum, bowel, and sigmoid contours were evaluated on the online-IMRT and pre-IMRT dose distributions at six dose levels (V10(Gy), V20(Gy), V30(Gy), V40(Gy), V42.8(Gy), and V45(Gy)). RESULTS: Online-IMRT compared to pre-IMRT significantly reduced the volume of healthy tissue irradiated to all dose levels, except V10(Gy). CONCLUSIONS: Online MRI guidance reduces healthy tissue involvement in patients with cervical cancer.

MRI/linac integration.

PURPOSE/OBJECTIVES: In radiotherapy the healthy tissue involvement still poses serious dose limitations. This results in sub-optimal tumour dose and complications. Daily image guided radiotherapy (IGRT) is the key development in radiation oncology to solve this problem. MRI yields superb soft-tissue visualization and provides several imaging modalities for identification of movements, function and physiology. Integrating MRI functionality with an accelerator can make these capacities available for high precision, real time IGRT. DESIGN AND RESULTS: The system being built at the University Medical Center Utrecht is a 1.5T MRI scanner, with diagnostic imaging functionality and quality, integrated with a 6MV radiotherapy accelerator. The realization of a prototype of this hybrid system is a joint effort between the Radiotherapy Department of the University of Utrecht, the Netherlands, Elekta, Crawley, U.K., and Philips Research, Hamburg, Germany. Basically, the design is a 1.5 T Philips Achieva MRI scanner with a Magnex closed bore magnet surrounded by a single energy (6 MV) Elekta accelerator. Monte Carlo simulations are used to investigate the radiation beam properties of the hybrid system, dosimetry equipment and for the construction of patient specific dose deposition kernels in the presence of a magnetic field. The latter are used to evaluate the IMRT capability of the integrated MRI linac. CONCLUSIONS: A prototype hybrid MRI/linac for on-line MRI guidance of radiotherapy (MRIgRT) is under construction. The aim of the system is to deliver the radiation dose with mm precision based on diagnostic quality MR images.

Benefit of adaptive CT-based treatment planning in high-dose-rate endorectal brachytherapy for rectal cancer.

PURPOSE: In this planning study, we investigated the dosimetric benefit of repeat CT-based treatment planning at each fraction vs. the use of a single CT-based treatment plan for all fractions for high-dose-rate endorectal brachytherapy (HDREBT) for rectal cancer. METHODS AND MATERIALS: We included 11 patients that received a CT scan with applicator in situ for all three fractions. The treatment plan of the first fraction was projected on the repeat CT scans to simulate the use of a single treatment plan. In addition, replanning was performed on the repeat CT scans, and these were compared to the corresponding projected treatment plans. RESULTS: Repeat CT-based treatment planning resulted on average in a 21% higher (p = 0.01) conformity index compared to single CT-based treatment planning. Projecting the initial treatment plan to the repeat CT scans of fraction two and three, 12/22 fractions reached a CTV D98 of 85% of the prescribed dose of 7 Gy, which increased to 14/22 using replanning. For the remaining fractions, median CTV D98 was 4.2 Gy, and an intervention would be necessary to correct applicator balloon setup or to remove remaining air and/or feces between the CTV and the applicator. CONCLUSIONS: Using a single CT-based treatment plan for all fractions may result in a suboptimal treatment at later fractions. Therefore, repeat CT imaging should be the minimal standard practice in HDREBT for rectal cancer to determine whether an intervention would be necessary. Replanning based on repeat CT imaging resulted in more conformal treatment plans and is therefore recommended.

Intrafraction motion in patients with cervical cancer: The benefit of soft tissue registration using MRI.

BACKGROUND AND PURPOSE: During radiation delivery, target volumes change their position and shape due to intrafraction motion. The extent of these changes and the capability to correct for them will contribute to the benefit of an MRI-accelerator in terms of PTV margin reduction. Therefore, we investigated the primary CTV motion within a typical IMRT delivery time for cervical cancer patients for various correction techniques: no registration, rigid bony anatomy registration, and rigid soft tissue registration. MATERIALS AND METHODS: Twenty-two patients underwent 2-3 offline MRI exams before and during their radiation treatment. Each MRI exam included four sagittal and four axial MRI scans alternately within 16min. We addressed the CTV motion by comparing subsequent midsagittal CTV delineations and investigated the correlation with intrafraction bladder filling. RESULTS: The maximum (residual) motions within 16min for all points on the CTV contour for 90% of the MRI exams without registration, with rigid bony anatomy registration, and with rigid soft tissue registration were 10.6, 9.9, and 4.0mm. A significant but weak correlation was found between intrafraction bladder filling and CTV motion. CONCLUSIONS: Considerable intrafraction CTV motion is observed in cervical cancer patients. Intrafraction MRI-guided soft tissue registration using an MRI-accelerator will correct for this motion.