Stereotactic MR-guided on-table adaptive radiation therapy (SMART) for borderline resectable and locally advanced pancreatic cancer: A multi-center, open-label phase 2 study.

BACKGROUND AND PURPOSE: Radiation dose escalation may improve local control (LC) and overall survival (OS) in select pancreatic ductal adenocarcinoma (PDAC) patients. We prospectively evaluated the safety and efficacy of ablative stereotactic magnetic resonance (MR)-guided adaptive radiation therapy (SMART) for borderline resectable (BRPC) and locally advanced pancreas cancer (LAPC). The primary endpoint of acute grade ≥ 3 gastrointestinal (GI) toxicity definitely related to SMART was previously published with median follow-up (FU) 8.8 months from SMART. We now present more mature outcomes including OS and late toxicity. MATERIALS AND METHODS: This prospective, multi-center, single-arm open-label phase 2 trial (NCT03621644) enrolled 136 patients (LAPC 56.6 %; BRPC 43.4 %) after ≥ 3 months of any chemotherapy without distant progression and CA19-9 ≤ 500 U/mL. SMART was delivered on a 0.35 T MR-guided system prescribed to 50 Gy in 5 fractions (biologically effective dose10 [BED10] = 100 Gy). Elective coverage was optional. Surgery and chemotherapy were permitted after SMART. RESULTS: Mean age was 65.7 years (range, 36-85), induction FOLFIRINOX was common (81.7 %), most received elective coverage (57.4 %), and 34.6 % had surgery after SMART. Median FU was 22.9 months from diagnosis and 14.2 months from SMART, respectively. 2-year OS from diagnosis and SMART were 53.6 % and 40.5 %, respectively. Late grade ≥ 3 toxicity definitely, probably, or possibly attributed to SMART were observed in 0 %, 4.6 %, and 11.5 % patients, respectively. CONCLUSIONS: Long-term outcomes from the phase 2 SMART trial demonstrate encouraging OS and limited severe toxicity. Additional prospective evaluation of this novel strategy is warranted.

A multi-centric evaluation of self-learning GAN based pseudo-CT generation software for low field pelvic magnetic resonance imaging.

Purpose/objectives: An artificial intelligence-based pseudo-CT from low-field MR images is proposed and clinically evaluated to unlock the full potential of MRI-guided adaptive radiotherapy for pelvic cancer care. Materials and method: In collaboration with TheraPanacea (TheraPanacea, Paris, France) a pseudo-CT AI-model was generated using end-to-end ensembled self-supervised GANs endowed with cycle consistency using data from 350 pairs of weakly aligned data of pelvis planning CTs and TrueFisp-(0.35T)MRIs. The image accuracy of the generated pCT were evaluated using a retrospective cohort involving 20 test cases coming from eight different institutions (US: 2, EU: 5, AS: 1) and different CT vendors. Reconstruction performance was assessed using the organs at risk used for treatment. Concerning the dosimetric evaluation, twenty-nine prostate cancer patients treated on the low field MR-Linac (ViewRay) at Montpellier Cancer Institute were selected. Planning CTs were non-rigidly registered to the MRIs for each patient. Treatment plans were optimized on the planning CT with a clinical TPS fulfilling all clinical criteria and recalculated on the warped CT (wCT) and the pCT. Three different algorithms were used: AAA, AcurosXB and MonteCarlo. Dose distributions were compared using the global gamma passing rates and dose metrics. Results: The observed average scaled (between maximum and minimum HU values of the CT) difference between the pCT and the planning CT was 33.20 with significant discrepancies across organs. Femoral heads were the most reliably reconstructed (4.51 and 4.77) while anal canal and rectum were the less precise ones (63.08 and 53.13). Mean gamma passing rates for 1%1mm, 2%/2mm, and 3%/3mm tolerance criteria and 10% threshold were greater than 96%, 99% and 99%, respectively, regardless the algorithm used. Dose metrics analysis showed a good agreement between the pCT and the wCT. The mean relative difference were within 1% for the target volumes (CTV and PTV) and 2% for the OARs. Conclusion: This study demonstrated the feasibility of generating clinically acceptable an artificial intelligence-based pseudo CT for low field MR in pelvis with consistent image accuracy and dosimetric results.

A Multi-Institutional Phase 2 Trial of Ablative 5-Fraction Stereotactic Magnetic Resonance-Guided On-Table Adaptive Radiation Therapy for Borderline Resectable and Locally Advanced Pancreatic Cancer.

PURPOSE: Magnetic resonance (MR) image guidance may facilitate safe ultrahypofractionated radiation dose escalation for inoperable pancreatic ductal adenocarcinoma. We conducted a prospective study evaluating the safety of 5-fraction Stereotactic MR-guided on-table Adaptive Radiation Therapy (SMART) for locally advanced (LAPC) and borderline resectable pancreatic cancer (BRPC). METHODS AND MATERIALS: Patients with LAPC or BRPC were eligible for this multi-institutional, single-arm, phase 2 trial after ≥3 months of systemic therapy without evidence of distant progression. Fifty gray in 5 fractions was prescribed on a 0.35T MR-guided radiation delivery system. The primary endpoint was acute grade ≥3 gastrointestinal (GI) toxicity definitely attributed to SMART. RESULTS: One hundred thirty-six patients (LAPC 56.6%, BRPC 43.4%) were enrolled between January 2019 and January 2022. Mean age was 65.7 (36-85) years. Head of pancreas lesions were most common (66.9%). Induction chemotherapy mostly consisted of (modified)FOLFIRINOX (65.4%) or gemcitabine/nab-paclitaxel (16.9%). Mean CA19-9 after induction chemotherapy and before SMART was 71.7 U/mL (0-468). On-table adaptive replanning was performed for 93.1% of all delivered fractions. Median follow-up from diagnosis and SMART was 16.4 and 8.8 months, respectively. The incidence of acute grade ≥3 GI toxicity possibly or probably attributed to SMART was 8.8%, including 2 postoperative deaths that were possibly related to SMART in patients who had surgery. There was no acute grade ≥3 GI toxicity definitely related to SMART. One-year overall survival from SMART was 65.0%. CONCLUSIONS: The primary endpoint of this study was met with no acute grade ≥3 GI toxicity definitely attributed to ablative 5-fraction SMART. Although it is unclear whether SMART contributed to postoperative toxicity, we recommend caution when pursuing surgery, especially with vascular resection after SMART. Additional follow-up is ongoing to evaluate late toxicity, quality of life, and long-term efficacy.

MRI-LINAC: A transformative technology in radiation oncology.

Advances in radiotherapy technologies have enabled more precise target guidance, improved treatment verification, and greater control and versatility in radiation delivery. Amongst the recent novel technologies, Magnetic Resonance Imaging (MRI) guided radiotherapy (MRgRT) may hold the greatest potential to improve the therapeutic gains of image-guided delivery of radiation dose. The ability of the MRI linear accelerator (LINAC) to image tumors and organs with on-table MRI, to manage organ motion and dose delivery in real-time, and to adapt the radiotherapy plan on the day of treatment while the patient is on the table are major advances relative to current conventional radiation treatments. These advanced techniques demand efficient coordination and communication between members of the treatment team. MRgRT could fundamentally transform the radiotherapy delivery process within radiation oncology centers through the reorganization of the patient and treatment team workflow process. However, the MRgRT technology currently is limited by accessibility due to the cost of capital investment and the time and personnel allocation needed for each fractional treatment and the unclear clinical benefit compared to conventional radiotherapy platforms. As the technology evolves and becomes more widely available, we present the case that MRgRT has the potential to become a widely utilized treatment platform and transform the radiation oncology treatment process just as earlier disruptive radiation therapy technologies have done.

The initial experience of MRI-guided precision prone breast irradiation with daily adaptive planning in treating early stage breast cancer patients.

Background: A major challenge in breast radiotherapy is accurately targeting the surgical cavity volume. Application of the emerging MRI-guided radiotherapy (MRgRT) technique in breast radiotherapy may enable more accurate targeting and potentially reduce side effects associated with treatment. Purpose: To study the feasibility of delivering MRI-guided partial breast radiotherapy or Precision Prone Irradiation (PPI) to treat DCIS and early stage breast cancer patients. Materials and methods: Eleven patients with diagnosed DCIS or early stage breast cancer treated with lumpectomy underwent CT-based and MRI-based simulations and treatment planning in the prone position. MRI-guided radiotherapy was utilized to deliver partial breast irradiation. A customized adaptive plan was created for each delivered radiotherapy fraction and the cumulative doses to the target volumes and nearby organs at risk were determined. The CT-based and the MRI-guided radiotherapy plans were compared with respect to target volumes, target volume coverage, and dose to nearby organs. Results: All patients receiving PPI successfully completed their treatments as planned. Clinical target volume (CTV) and planning target volume (PTV) dose coverage and organs-at-risk (OAR) dose constraints were met in all fractions planned and delivered and the MRI-guided clinical target volumes were smaller when compared to those of the CT-based partial breast radiotherapy plans for these eleven patients. Conclusions: MRI-guided partial breast radiotherapy as a breast radiotherapy technology is feasible and is a potential high clinical impact application of MRgRT. PPI has the potential to improve the therapeutic index of breast radiotherapy by more accurately delivering radiation dose to the cavity target and decreasing toxicities associated with radiation to the surrounding normal tissues. Prospective clinical data and further technical refinements of this novel technology may broaden its clinical implementation.

Quantifying the impact of SpaceOAR hydrogel on inter-fractional rectal and bladder dose during 0.35 T MR-guided prostate adaptive radiotherapy.

PURPOSE: To investigate the impact of rectal spacing on inter-fractional rectal and bladder dose and the need for adaptive planning in prostate cancer patients undergoing SBRT with a 0.35 T MRI-Linac. MATERIALS AND METHODS: We evaluated and compared SBRT plans from prostate cancer patients with and without rectal spacer who underwent treatment on a 0.35 T MRI-Linac. Each group consisted of 10 randomly selected patients that received prostate SBRT to a total dose of 36.25 Gy in five fractions. Dosimetric differences in planned and delivered rectal and bladder dose and the number of fractions violating OAR constraints were quantified. We also assessed whether adaptive planning was needed to meet constraints for each fraction. RESULTS: On average, rectal spacing reduced the maximum dose delivered to the rectum by more than 8 Gy (p < 0.001). We also found that D3cc received by the rectum could be 12 Gy higher in patients who did not have rectal spacer (p < 9E-7). In addition, the results show that a rectal spacer can reduce the maximum dose and D15cc to the bladder wall by more than 1 (p < 0.004) and 8 (p < 0.009) Gy, respectively. Our study also shows that using a rectal spacer could reduce the necessity for adaptive planning. The incidence of dose constraint violation was observed in almost 91% of the fractions in patients without the rectal spacer and 52% in patients with implanted spacer. CONCLUSION: Inter-fractional changes in rectal and bladder dose were quantified in patients who underwent SBRT with/without rectal SpaceOAR hydrogel. Rectal spacer does not eliminate the need for adaptive planning but reduces its necessity.

Is there a role for an external beam boost in cervical cancer radiotherapy?

OBJECTIVES: Some patients are medically unfit for or averse to undergoing a brachytherapy boost as part of cervical cancer radiotherapy. In order to be able to definitively treat these patients, we assessed whether we could achieve a boost plan that would mimic our brachytherapy plans using external beam radiotherapy. METHODS: High dose rate brachytherapy plans of 20 patients with stage IIB cervical cancer treated with definitive chemoradiotherapy were included in this study. Patients had undergone computer tomography (CT) simulations with tandem and ovoids in place. Point "A" dose was 600-700 cGy. We attempted to replicate the boost dose distribution from brachytherapy plans using intensity-modulated radiotherapy (Varian Medical Systems, Palo Alto, CA, USA), volumetric modulated arc therapy (Rapid Arc, Varian Medical Systems, Palo Alto, CA, USA), or TomoTherapy (Accuray, Inc., Sunnyvale, CA, USA) with the brachytherapy 100% isodose line as our target. Target coverage, normal tissue dose, and brachytherapy point doses were compared with ANOVA. Two-sided p-values ≤0.05 were considered significant. RESULTS: External beam plans had excellent planning target volume (PTV) coverage, with no difference in mean PTV V95% among planning techniques (range 98-100%). External beam plans had lower bladder Dmax, small intestine Dmax, and vaginal mucosal point dose than brachytherapy plans, with no difference in bladder point dose, mean bladder dose, mean small intestine dose, or rectal dose. Femoral head dose, parametria point dose, and pelvic sidewall point dose were higher with external beam techniques than brachytherapy. CONCLUSIONS: External beam plans had comparable target coverage and potential for improved sparing of most normal tissues compared to tandem and ovoid brachytherapy.

Combining aminocyanine dyes with polyamide dendrons: a promising strategy for imaging in the near-infrared region.

Cyanine dyes are known for their fluorescence in the near-IR (NIR) region, which is desirable for biological applications. We report the synthesis of a series of aminocyanine dyes containing terminal functional groups such as acid, azide, and cyclooctyne groups for further functionalization through, for example, click chemistry. These aminocyanine dyes can be attached to polyfunctional dendrons by copper-catalyzed azide alkyne cycloaddition (CuAAC), strain-promoted azide alkyne cycloaddition (SPAAC), peptide coupling, or direct S(NR)1 reactions. The resulting dendron-dye conjugates were obtained in high yields and displayed high chemical stability and photostability. The optical properties of the new compounds were studied by UV/Vis and fluorescence spectroscopy. All compounds show large Stokes shifts and strong fluorescence in the NIR region with high quantum yields, which are optimal properties for in vivo optical imaging.

Construction of a well-defined multifunctional dendrimer for theranostics.

A dendrimer-based building block for theranostics was designed. The multifunctional dendrimer is polyamide-based and contains nine azide termini, nine amine termini, and fifty-four terminal acid groups. Orthogonal functionalization of the multifunctional dendrimer with a near-infrared (NIR) cyanine dye afforded the final dendrimer that shows fluorescence in the NIR region and no toxicity toward T98G human cells. The synthetic strategy described here might be promising for fabricating the next generation of materials for theranostics.

Electrochromic polymer films containing Re(I) and Pt(II) metal centers.

Three Re(I) complexes (3, 5, and 7) (Re(CO)3Cl(L)2) and three new Pt(II) complexes (4, 6, and 8) ([Pt(P(Et)3)2(L)2](OTf)2), where L = pyridine, 1 (4-Py-EDOT) or 2 (4-Py-bithiophene), were prepared and characterized. The solid-state structures of 4 and 5 were determined by X-ray crystallography. Electrochromic polymeric films of 2, 5, and 6 were prepared and characterized.