Fertility-sparing uterine displacement for pelvic malignancies: surgical options and radiotherapy dosimetry on a human cadaver.

BACKGROUND: Radio(chemo)therapy is often required in pelvic malignancies (cancer of the anus, rectum, cervix). Direct irradiation adversely affects ovarian and endometrial function, compromising the fertility of women. While ovarian transposition is an established method to move the ovaries away from the radiation field, surgical procedures to displace the uterus are investigational. This study demonstrates the surgical options for uterine displacement in relation to the radiation dose received.  METHODS: The uterine displacement techniques were carried out sequentially in a human female cadaver to demonstrate each procedure step by step and assess the uterine positions with dosimetric CT scans in a hybrid operating room. Two treatment plans (anal and rectal cancer) were simulated on each of the four dosimetric scans (1. anatomical position, 2. uterine suspension of the round ligaments to the abdominal wall 3. ventrofixation of the uterine fundus at the umbilical level, 4. uterine transposition). Treatments were planned on Eclipse® System (Varian Medical Systems®,USA) using Volumetric Modulated Arc Therapy. Data about maximum (Dmax) and mean (Dmean) radiation dose received and the volume receiving 14 Gy (V14Gy) were collected. RESULTS: All procedures were completed without technical complications. In the rectal cancer simulation with delivery of 50 Gy to the tumor, Dmax, Dmean and V14Gy to the uterus were respectively 52,8 Gy, 34,3 Gy and 30,5cc (1), 31,8 Gy, 20,2 Gy and 22.0cc (2), 24,4 Gy, 6,8 Gy and 5,5cc (3), 1,8 Gy, 0,6 Gy and 0,0cc (4). For anal cancer, delivering 64 Gy to the tumor respectively 46,7 Gy, 34,8 Gy and 31,3cc (1), 34,3 Gy, 20,0 Gy and 21,5cc (2), 21,8 Gy, 5,9 Gy and 2,6cc (3), 1,4 Gy, 0,7 Gy and 0,0cc (4). CONCLUSIONS: The feasibility of several uterine displacement procedures was safely demonstrated. Increasing distance to the radiation field requires more complex surgical interventions to minimize radiation exposure. Surgical strategy needs to be tailored to the multidisciplinary treatment plan, and uterine transposition is the most technically complex with the least dose received.

Comparative study of dynamic conformal arc therapy and volumetric modulated arc therapy for treating single brain metastases: A retrospective analysis of dosimetric and clinical outcomes.

Background and purpose: Stereotactic radiation therapy (SRT) is commonly used to treat brain metastases (BMs). This retrospective study compared two SRT techniques, dynamic conformal arc therapy (DCAT) and volumetric modulated arc therapy (VMAT), for single BM treatments. Material and methods: Data of patients treated between January 2010 and June 2020 were considered. Patients with multiple BMs, resected BMs, reirradiation, whole-brain radiation therapy and brainstem metastases were excluded. We focused our analysis on 97 patients who received 23.1 Gy in three fractions. Acute toxicities and follow-up outcomes were recorded. Dosimetric data were analyzed in two subgroups (PTV ≤ 10 cc and PTV > 10 cc). Results: DCAT and VMAT were used in 70 (72.2 %) and 27 (27.8 %) patients, respectively. Acute toxicities were not significantly different between groups (p = 0.259), and no difference was detected in the incidence rate of radionecrosis, local recurrence and cerebral recurrence (p > 0.999, p > 0.999 and p = 0.682, respectively). PTV coverage was better with DCAT for small volumes (PTV ≤ 10 cc). Mean conformity index (CI) was significantly higher with VMAT and mean gradient index (GI) was significantly lower with DCAT whatever volume subgroups (p < 0.001). DCAT had more heterogeneous plans and VMAT required more monitor units. DCAT resulted in reduced low and intermediate doses, whereas VMAT led to decreased high doses. Conclusion: DCAT and VMAT are two effective and safe SRT techniques for BMs treatment. In the era of re-irradiation, it is important to reduce the doses delivered to healthy tissues. Further prospective studies are needed to validate these findings.

Influence of the Planning Parameters of a New Algorithm on the Dosimetric Quality, Beam-On Time and Delivery Accuracy of Tomotherapy Plans.

BACKGROUND: This work aimed to determine the optimum VOLOTM Ultra algorithm parameters for tomotherapy treatments. METHODS: 1056 treatment plans were generated with VOLOTM Ultra for 36 patients and six anatomical locations. The impact of varying four parameters was studied: the accelerated treatment (AT), leaf open/close time (LOT) cutoff, normal tissue objective (NTO) weight, and number of iterations. The beam-on time and dosimetric metrics were quantified for the target volumes and organs at risk (OARs). Delivery quality assurance measurements were obtained for 36 plans to assess the delivery accuracy. RESULTS: The mean beam-on time for the helical tomotherapy and TomoDirect (TD) plans decreased by 26.6 ± 2.8% and 17.4 ± 4.3%, respectively, when the accelerated treatment parameter was increased from 0 to 10, at the expense of the planning target volume (PTV) coverage (2% lower D98%) and OAR dose (up to 15% increase). For TD plans, it seems preferable to systematically use an AT value of 10. Increasing the number of iterations beyond six seems unnecessary. In this study, an NTO weight of approximately 10 appears to be ideal and eliminates the need to use rings in the treatment plan. Finally, no correlation was found between the leaf open/close time cutoff and the delivery accuracy, while a leaf open/close cutoff of 60 ms seemed to degrade dosimetry quality. CONCLUSION: Optimal values for the AT, LOT cutoff, NTO weight, and number of optimization rounds were identified and should help improve the management of patients whose tomotherapy treatments are planned with VOLOTM Ultra.

Repeated Stereotactic Radiotherapy for Local Brain Metastases Failure or Distant Brain Recurrent: A Retrospective Study of 184 Patients.

BACKGROUND: The main advantages of stereotactic radiotherapy (SRT) are to delay whole-brain radiotherapy (WBRT) and to deliver ablative doses. Despite this efficacy, the risk of distant brain metastases (BM) one year after SRT ranges from 26% to 77% and 20 to 40% of patients required salvage treatment. The role and consequences of reirradiation remain unclear, particularly in terms of survival. The objective was to study overall survival (OS) and neurological death-free survival (NDFS) and to specify the prognostic factors of long-term survival. METHODS: we retrospectively reviewed the data of patients treated between 2010 and 2020 with at least two courses of SRT without previous WBRT. RESULTS: In total, 184 patients were treated for 915 BMs with two-to-six SRT sessions. Additional SRT sessions were provided for local (5.6%) or distant (94.4%) BM recurrence. The median number of BMs treated per SRT was one with a median of four BMs in total. The mean time between the two SRT sessions was 8.9 months (95%CI 7.7-10.1) and there was no significant difference in the delay between the two sessions. The 6-, 12- and 24-month NDFS rates were 97%, 82% and 52%, respectively. The 6-, 12- and 24-month OS rates were 91%, 70% and 38%, respectively. OS was statistically related to the number of SRT sessions (HR = 0.48; p < 0.01), recursive partitioning analysis (HR = 1.84; p = 0.01), salvage WBRT (HR = 0.48; p = 0.01) and brain metastasis velocity (high: HR = 13.83; p < 0.01; intermediate: HR = 4.93; p < 0.01). CONCLUSIONS: Lung cancer and melanoma were associated with a lower NDFS compared to breast cancer. A low KPS, a low number of SRT sessions, synchronous extracerebral metastases, synchronous BMs, extracerebral progression at SRT1, a high BMV grade, no WBRT and local recurrence were also associated with a lower NDFS. A high KPS at SRT1 and low BMV grade are prognostic factors for better OS, regardless of the number of BM recurrence events.

Stereotactic Radiation Therapy of Single Brain Metastases: A Literature Review of Dosimetric Studies.

Stereotactic radiotherapy (SRT) plays a major role in treating brain metastases (BMs) and can be delivered using various equipment and techniques. This review aims to identify the dosimetric factors of each technique to determine whether one should be preferred over another for single BMs treatment. A systematic literature review on articles published between January 2015 and January 2022 was conducted using the MEDLINE and ScienceDirect databases, following the PRISMA methodology, using the keywords "dosimetric comparison" and "brain metastases". The included articles compared two or more SRT techniques for treating single BM and considered at least two parameters among: conformity (CI), homogeneity (HI) and gradient (GI) indexes, delivery treatment time, and dose-volume of normal brain tissue. Eleven studies were analyzed. The heterogeneous lesions along with the different definitions of dosimetric indexes rendered the studied comparison almost unattainable. Gamma Knife (GK) and volumetric modulated arc therapy (VMAT) provide better CI and GI and ensure the sparing of healthy tissue. To conclude, it is crucial to optimize dosimetric indexes to minimize radiation exposure to healthy tissue, particularly in cases of reirradiation. Consequently, there is a need for future well-designed studies to establish guidelines for selecting the appropriate SRT technique based on the treated BMs' characteristics.

Local recurrence and cerebral progression-free survival after multiple sessions of stereotactic radiotherapy of brain metastases: a retrospective study of 184 patients : Statistical analysis.

PURPOSE: Forty to sixty percent of patients treated with focal therapy for brain metastasis (BM) will have distant brain recurrence (C-LR), while 10-25% of patients will have local recurrence (LR) within 1 year after stereotactic radiotherapy (SRT). The purpose of this study was to analyze cerebral progression-free survival (C-PFS) and LR of BM among patients treated with repeated courses of radiotherapy in stereotactic conditions. METHODS AND MATERIALS: We retrospectively reviewed data from 184 patients treated for 915 BMs with at least two courses of SRT without previous WBRT. Initial patient characteristics, patient characteristics at each SRT, brain metastasis velocity (BMV), delay between SRT, MRI response, LR and C­LR were analyzed. RESULTS: In all, 123 (66.9%), 39 (21.2%), and 22 (12%) patients received 2, 3, or 4 or more SRT sessions, respectively. Ninety percent of BMs were irradiated without prior surgery, and 10% were irradiated after neurosurgery. The MRI response at 3, 6, 12 and 24 months after SRT was stable regardless of the SRT session. At 6, 12 and 24 months, the rates of local control were 96.3, 90.1, and 85.8%, respectively. In multivariate analysis, P­LR was statistically associated with kidney (HR = 0.08) and lung cancer (HR = 0.3), ECOG 1 (HR = 0.5), and high BMV grade (HR = 5.6). The median C­PFS after SRT1, SRT2, SRT3 and SRT4 and more were 6.6, 5.1, 6.7, and 7.7 months, respectively. C­PFS after SRT2 was significantly longer among patients in good general condition (HR = 0.39), patients with high KPS (HR = 0.91), patients with no extracerebral progression (HR = 1.8), and patients with a low BMV grade (low vs. high: HR = 3.8). CONCLUSION: Objective MRI response rate after repeated SRT is stable from session to session. Patients who survive longer, such as patients with breast cancer or with low BMV grade, are at risk of local reirradiation. C­PFS after SRT2 is better in patients in good general condition, without extracerebral progression and with low BMV grade.

Radiosensitizing Pancreatic Cancer with PARP Inhibitor and Gemcitabine: An In Vivo and a Whole-Transcriptome Analysis after Proton or Photon Irradiation.

Over the past few years, studies have focused on the development of targeted radiosensitizers such as poly(ADP-ribose) polymerase inhibitors. We performed an in vivo study and a whole-transcriptome analysis to determine whether PARP inhibition enhanced gemcitabine-based chemoradiosensitization of pancreatic cancer xenografts, combined with either proton or photon irradiation. NMRI mice bearing MIA PaCa-2 xenografts were treated with olaparib and/or gemcitabine and irradiated with 10 Gy photon or proton. First, a significant growth inhibition was obtained after 10 Gy proton irradiation compared to 10 Gy photon irradiation (p = 0.046). Moreover, the combination of olaparib, gemcitabine and proton therapy significantly sensitized tumor xenografts, compared to gemcitabine (p = 0.05), olaparib (p = 0.034) or proton therapy (p < 0.0001) alone or to the association of olaparib, gemcitabine and radiotherapy (p = 0.024). Simultaneously, whole RNA sequencing profiling showed differentially expressed genes implicated in categories such as DNA repair, type I interferon signaling and cell cycle. Moreover, a large amount of lncRNA was dysregulated after proton therapy, gemcitabine and olaparib. This is the first study showing that addition of olaparib to gemcitabine-based chemoradiotherapy improved significantly local control in vivo, especially after proton therapy. RNA sequencing profiling analysis presented dynamic alteration of transcriptome after chemoradiation and identified a classifier of gemcitabine response.

Automatic detection and segmentation of brain metastases on multimodal MR images with a deep convolutional neural network.

Stereotactic treatments are today the reference techniques for the irradiation of brain metastases in radiotherapy. The dose per fraction is very high, and delivered in small volumes (diameter <1 cm). As part of these treatments, effective detection and precise segmentation of lesions are imperative. Many methods based on deep-learning approaches have been developed for the automatic segmentation of gliomas, but very little for that of brain metastases. We adapted an existing 3D convolutional neural network (DeepMedic) to detect and segment brain metastases on MRI. At first, we sought to adapt the network parameters to brain metastases. We then explored the single or combined use of different MRI modalities, by evaluating network performance in terms of detection and segmentation. We also studied the interest of increasing the database with virtual patients or of using an additional database in which the active parts of the metastases are separated from the necrotic parts. Our results indicated that a deep network approach is promising for the detection and the segmentation of brain metastases on multimodal MRI.

Megavoltage 2D topographic imaging: An attractive alternative to megavoltage CT for the localization of breast cancer patients treated with TomoDirect.

PURPOSE: To show the usefulness of topographic 2D megavoltage images (MV2D) for the localization of breast cancer patients treated with TomoDirect (TD), a radiotherapy treatment technique with fixed-angle beams performed on a TomoTherapy system. METHODS: A method was developed to quickly localize breast cancer patients treated with TD by registering the MV2D images produced before a TD treatment with reference images reconstructed from a kilovoltage CT simulation scanner and by using the projection of the beam-eye-view TD treatment field. Dose and image quality measurements were performed to determine the optimal parameters for acquiring MV2D images. A TD treatment was simulated on a chest phantom equipped with a breast attachment. MVCT and MV2D images were performed for 7 different shifted positions of the phantom and registered by 10 different operators with the simulation kilovoltage CT images. RESULTS: Compared to MVCT, MV2D imaging reduces the dose by a factor of up to 45 and the acquisition time by a factor of up to 49. Comparing the registration shift values obtained for the phantom images obtained with MVCT in the coarse mode to those obtained with MV2D, the mean difference is 1.0±1.1mm, -1.1mm±1.1, and -0.1±2.2mm, respectively, in the lateral, longitudinal, and vertical directions. CONCLUSIONS: With dual advantages (very fast imaging and a potentially reduced dose to the heart and contralateral organs), MV2D topographic images may be an attractive alternative to MVCT for the localization of breast cancer patients treated with TomoDirect.

Is the lack of respiratory gating prejudicial for left breast TomoDirect treatments?

BACKGROUND AND PURPOSE: TomoDirect (TD) can only operate in free-breathing. The purpose of this study is to compare TD with breath-hold 3D conformal radiotherapy (3DCRT) and intensity modulated radiotherapy (IMRT) techniques for left breast treatments, and to determine if the lack of respiratory gating is a handicap for cardiac sparing. MATERIALS AND METHODS: 15 patients treated for left breast had two computed tomography simulation, in free breathing (FB) and in deep-inspiration breath-hold (DIBH). Four treatments were planned: TD-FB, 3DCRT-FB, 3DCRT-DIBH and IMRT-DIBH. Dose to PTV, heart, lungs, right breast and patient were compared. RESULTS: A slightly lower cardiac mean dose is found for 3DCRT-DIBH than for TD-FB group (1.99Gy Vs 2.89Gy, p=0.0462), while no statistical difference is found for heart V20. TD-FB plans show the best PTV dose homogeneity (0.053, p<0.001) and the lowest left lung mean dose (5.16Gy, p<0.001). No major differences are found for the other organs. CONCLUSIONS: TomoDirect and breath-hold 3DCRT are complementary techniques for left breast treatments: for a minority of patients, respiratory gating is mandatory to lower cardiac dose; for the remaining majority of patients, TomoDirect achieves better PTV homogeneity and reduced left lung dose, with cardiac dose equivalent to 3DCRT-DIBH.

The optimal tomotherapy treatment planning parameters for extremity soft tissue sarcomas.

BACKGROUND AND PURPOSE: To determine the optimum combination of treatment parameters between pitch, field width (FW) and modulation factor (MF) for extremity sarcomas in tomotherapy. MATERIALS AND METHODS: Six patients previously treated for extremity sarcomas (3 arms and 3 legs) with tomotherapy were included in this study. 288 treatment plans were recalculated, corresponding to all combinations between 2 FW (2.5 and 5 cm), 4 MF (1.5, 2, 2.5 and 3) and 6 pitches (0.215, 0.287, 0.43 and 3 off-axis pitches). The treatment parameters (MF, FW or pitch) are modified between each plan, and the calculation is relaunched for 400 iterations, without modifying the optimisation constraints of the plan under which the patient has been treated. RESULTS: We suggest eliminating the 0.43 pitch and never combining a 0.215 pitch with an MF ≤ 2. We also do not recommend using an MF = 1.5 unless treatment time is an absolute priority over plan quality. We did not see any advantage in using Chen off-axis pitches, except for targets far from the axis (>15 cm) treated with a high pitch. A combination of MF = 2/FW = 5 cm/pitch = 0.287 gives plans of acceptable quality, combined with reduced treatment times. These conclusions are true only for extremity sarcomas treated in 2 Gy/fraction. CONCLUSIONS: We have shown that the choice of pitch/MF/FW combination is crucial for the treatment of extremity sarcomas in tomotherapy: some produce good dosimetric quality with a reduced irradiation time, while others may increase the time without improving the quality.

External irradiation models for intracranial 9L glioma studies.

PURPOSE: Radiotherapy has been shown to be an effective for the treatment human glioma and consists of 30 fractions of 2 Gy each for 6-7 weeks in the tumor volume with margins. However. in preclinical studies, many different radiation schedules are used. The main purpose of this work was to review the relevant literature and to propose an external whole-brain irradiation (WBI) protocol for a rat 9L glioma model. MATERIALS AND METHODS: 9L cells were implanted in the striatum of twenty 344-Fisher rats to induce a brain tumor. On day 8, animals were randomized in two groups: an untreated group and an irradiated group with three fractions of 6 Gy at day 8, 11 and 14. Survival and toxicity were assessed. RESULTS: Irradiated rats had significantly a longer survival (p = 0.01). No deaths occurred due to the treatment. Toxicities of reduced weight and alopecia were increased during the radiation period but no serious morbidity or mortality was observed. Moreover, abnormalities disappeared the week following the end of the therapeutic schedule. CONCLUSIONS: Delivering 18 Gy in 3 fractions of 6 Gy every 3 days, with mild anaesthesia, is safe, easy to reproduce and allows for standardisation in preclinical studies of different treatment regimens glioma rat model.

Local delivery of ferrociphenol lipid nanocapsules followed by external radiotherapy as a synergistic treatment against intracranial 9L glioma xenograft.

PURPOSE: The goal of the present study was to evaluate the efficacy of a new organometallic drug, ferrociphenol (Fc-diOH), in combination with external radiotherapy in intracerebral 9L glioma model. We tested the hypothesis that the combination of external radiotherapy with Fc-diOH could potentiate the action of this drug. METHODS: 9L cells were treated with Fc-diOH-LNCs (from 0.01 to 1 micromol/L) and irradiated with external radiotherapy (from 2 to 40 Gy). In vivo assessment was evaluated by the inoculation of 9L cells in Fisher rats. Chemotherapy with Fc-diOH-LNCs (0.36 mg/rat) was administered by means of convection-enhanced delivery (CED), and the treatment was followed by three irradiations of 6 Gy doses (total dose = 18 Gy). RESULTS: In vitro evaluations evidenced that a combined treatment with Fc-diOH-LNCs and irradiations showed synergistic antitumor activity on 9L cells. Combining cerebral irradiation with CED of Fc-diOH-LNCs led to a significantly longer survival and the existence of long-term survivors compared to Fc-diOH-LNCs-treated animals (p < 0.0001) and to the group treated with blank LNCs + radiotherapy (p = 0.0079). CONCLUSION: The synergistic effect between ferrociphenol-loaded LNCs and radiotherapy was due to a closely oxidative relationship. Upon these considerations, Fc-diOH-LNCs appear to be an efficient radiosensitive anticancer drug delivery system.

In vivo evaluation of intracellular drug-nanocarriers infused into intracranial tumours by convection-enhanced delivery: distribution and radiosensitisation efficacy.

The objective of the present study was to investigate the interest of convection-enhanced delivery (CED) for the administration of a nanocarrier-based radiosensitizing chemotherapy in the rat brain. Pursuing on newly developed lipid nanocapsules (LNC) that can be internalised within brain tumour cells, we studied their intracerebral distribution when labelled with fluorescent Nile red (NR). As paclitaxel (Px) represents an interesting radiosensitiser, we also evaluated the potential radiosensitising effects of Px-loaded LNC administered through CED in the 9L intracranial rat glioblastoma model. The distribution study demonstrated that CED injection of NR-loaded LNC (NR-LNC) improved significantly the volume of distribution of NR when matched with simple injection (by about 150 fold). It also reveals that the LNC perfusion of a whole tumour forming area inside the CNS (6 days after implantation of 10(3) 9L cells) is achievable through CED injection, whilst preserving the ability of LNC to reach the intracellular space of encountered tumour cells. Having established an animal model of encephalic irradiation close to the clinic (18 Gray in three fractions of six Gray at days 8, 11 and 14 after 9L cell implantation) we proved the feasibility of the combination of CED for the administration of drug-loaded LNC with external beam therapy. Although a single CED injection of Px-LNC at low Px dose (375 mug/kg of bodyweight) gave the best median survival (twice that of untreated controls), it underlines the need for optimisation. Hence, the possibility of grafting recognition moieties onto the LNC surface combined to their biocompatibility must be beneficial.