Biliary Adverse Events During Neoadjuvant Therapy for Pancreatic Cancer.

OBJECTIVE: To describe a high-volume experience with biliary drainage before neoadjuvant therapy (NAT) for patients with operable pancreatic cancer (PC) and characterize the association between biliary adverse events (BAEs) and patient outcome. BACKGROUND: Patients with PC presenting with biliary obstruction require durable decompression before NAT. METHODS: Patients with operable PC and tumor-associated biliary obstruction were examined and grouped by the presence or absence of a BAE during NAT. The incidence, timing, and management of BAEs are described, and outcomes, including the completion of all treatment and overall survival (OS), were compared. RESULTS: Of 426 patients who received pretreatment biliary decompression, 92 (22%) experienced at least 1 BAE during NAT, and 56 (13%) required repeat intervention on their biliary stent. The median duration of NAT was 161 days for all patients and was not different in the group that experienced BAEs. The median time from initial stent placement to BAE was 64 days. An interruption in the delivery of NAT (median 7 days) occurred in 25 (6%) of 426 patients. Among 426 patients, 290 (68%) completed all NAT, including surgery: 60 (65%) of 92 patients with BAE and 230 (69%) of 334 patients without BAE ( P =0.51). Among 290 patients who completed NAT and surgery, the median OS was 39 months, 26 months for the 60 patients with BAE, and 43 months for the 230 patients without BAE ( P =0.02). CONCLUSIONS: During extended multimodal NAT for PC, 22% of patients experienced a BAE. Although BAEs were not associated with a significant interruption of treatment, patients who experienced a BAE had worse OS.

CA19-9 Response to First-Line Neoadjuvant FOLFIRINOX and Second-Line Gemcitabine/Nab-Paclitaxel for Patients with Operable Pancreatic Cancer.

BACKGROUND: Response to second-line (2L) neoadjuvant therapy for operable pancreatic cancer (PC) is understudied. This study examined carbohydrate antigen 19-9 (CA19-9) response to first-line (1L) and 2L chemotherapy. METHODS: The study identified patients with operable PC and elevated CA19-9 (≥ 35 U/mL with total bilirubin < 2 mg/dL) who received 1L FOLFIRINOX (FFX). The patients were restaged after 2 months and based on response, received additional FFX or gemcitabine/nab-paclitaxel (GnP) as part of total neoadjuvant therapy. Response was defined as a decrease in tumor size on computed tomography (CT) imaging or a decline in CA19-9 of 50% or more and preserved performance status. RESULTS: For operable PC with an elevated CA19-9, 108 patients received 1L FFX. After 2 months of chemotherapy, the decision was made to continue FFX (FFX ≥ FFX) for 76 (70%) of the 108 patients and switch to GnP (FFX ≥ GnP)) for 32 (30%) of the patients. Of the 32 FFX ≥ GnP patients, 27 had no evidence of radiographic or biochemical (CA19-9) response to 1L FFX. Of these 27 patients, 26 (96%) demonstrated a response to 2L GnP. After 4 months of chemotherapy, 62 (82%) of the 76 FFX ≥ FFX patients had a CA19-9 response compared with 31 (97%) of the 32 FFX ≥ GnP patients (p = 0.04). CONCLUSIONS: Lack of biochemical response to 2 months of 1L FFX may identify a subgroup of patients with a very high rate of response to 2L GnP, emphasizing the importance of assessing treatment response at 2-month intervals.

Neoadjuvant chemotherapy for pancreatic cancer: Quality over quantity.

BACKGROUND AND OBJECTIVES: The ideal duration of neoadjuvant chemotherapy (NACT) in patients with localized pancreatic adenocarcinoma (PDAC) treated with curative intent is unclear. We sought to determine the prognostic significance of both duration of NACT and Carbohydrate Antigen 19-9 (CA19-9) normalization to NACT. METHODS: We examined patients with resectable and borderline resectable PDAC treated with NACT and chemoradiation. Patients were compared by NACT duration (2 vs. 4 months) and by CA19-9 normalization after NACT. RESULTS: Among 171 patients, 83 (49%) received 2 months of NACT, and 88 (51%) received 4 months. After NACT completion, 115 (67%) patients had persistently elevated CA19-9, and 56 (33%) had normalized. Of the 125 patients who had successful surgery, 73 (58%) had normalized CA19-9 postoperatively. Duration of NACT was not associated with overall survival (OS) while CA19-9 normalization after NACT (regardless of duration) was associated with improved OS (hazard ratio [HR] 0.56, 95% confidence interval [CI] 0.35-0.89, p = 0.02). Adjuvant chemotherapy was associated with improved OS among patients without CA19-9 normalization after NACT (HR 0.42, CI 0.20-0.86, p = 0.02) but not among those that normalized, independent of duration. CONCLUSIONS: CA19-9 normalization after NACT is a clinically significant endpoint of treatment; patients without CA19-9 normalization may benefit from additional therapy.

Updates and new directions in the use of radiation therapy for the treatment of pancreatic adenocarcinoma: dose, sensitization, and novel technology.

Panc reatic ductal adenocarcinoma (PDAC) is a devastating malignancy. There have been few advances that have substantially improved overall survival in the past several years. On its current trajectory, the deaths from PDAC are expected to cross that from all gastrointestinal cancers combined by 2030. Radiation therapy is a technically very complex modality that bridges multiple different treatment strategies. It represents a hybrid among advanced diagnostic imaging, local (often ablative) intervention, and heterogeneous biological mechanisms contributing to normal and oncologic cell kill. In this article, we bring an overview of the several promising strategies that are currently being investigated to improve outcomes using radiation therapy for patients with PDAC.

Online adaptive MR-guided stereotactic radiotherapy for unresectable malignancies in the upper abdomen using a 1.5T MR-linac.

BACKGROUND: Introduction of online adaptive MR-guided radiotherapy enables stereotactic body radiation therapy (SBRT) of upper abdominal tumors. This study aimed to evaluate the feasibility of MR-guided SBRT on a 1.5 T MR-linac in patients with unresectable upper abdominal malignancies. MATERIAL AND METHODS: Patients treated at the UMC Utrecht (April 2019 to December 2020) were identified in the prospective 'Multi-OutcoMe EvaluatioN of radiation Therapy Using the MR-linac' (MOMENTUM) study. Feasibility of treatment was arbitrarily defined as an on-table time interval of ≤60 min for >75% of delivered fractions and completion of >95% of fractions as scheduled, reflecting patient tolerability. Acute treatment-related toxicity was assessed at 3 months of follow-up and graded according to the National Cancer Institute Common Terminology Criteria of Adverse Events version 5.0. RESULTS: Twenty-five consecutive patients with a median follow-up time of 8 (range 4-23) months were treated with 35 Gray (n = 4) and 40 Gray (n = 21) in five fractions over 2 weeks. For all fractions, contours were adapted based on the daily anatomy and delivered within 47 min/fraction (range 30-74). In 98/117 fractions (84%), adapted treatment was completed within 1 h. All patients received the scheduled irradiation dose as planned. No acute grade 3 toxicity or higher was reported. Treatment resulted in pain alleviation in 11/13 patients. DISCUSSION: Online adaptive MR-guided SBRT on a 1.5 T MR-linac is feasible and well-tolerated in patients with unresectable upper abdominal malignancies. Dose escalation studies, followed by comparative studies, are needed to determine the optimal radiation dose for irradiation of upper abdominal malignancies.

Total Neoadjuvant Therapy for Operable Pancreatic Cancer.

BACKGROUND: Overall survival (OS) for operable pancreatic cancer (PC) is optimized when 4-6 months of nonsurgical therapy is combined with pancreatectomy. Because surgery renders the delivery of postoperative therapy uncertain, total neoadjuvant therapy (TNT) is gaining popularity. METHODS: We performed a retrospective cohort study of patients with operable PC and compared TNT with shorter course neoadjuvant therapy (SNT). Primary outcomes of interest included completion of neoadjuvant therapy (NT) and resection of the primary tumor, receipt of 5 months of nonsurgical therapy, and median OS. RESULTS: We reviewed 541 consecutive patients from 2009 to 2019 including 226 (42%) with resectable PC and 315 (58%) with borderline resectable (BLR) PC. The median age was 66 years (IQR [59, 72]), and 260 (48%) patients were female. TNT was administered to 89 (16%) patients and SNT was administered to 452 (84%). Both groups were equally likely to complete intended NT and surgery (p = 0.90). Patients who received TNT and surgical resection were more likely to have a complete pathologic response (8% vs 4%, p < 0.01) and were more likely to receive at least 5 months of nonsurgical therapy (67% vs 45%, p < 0.01). The median OS was 26 months [IQR (15, 57)]; not reached among patients treated with TNT, and 25 months [IQR (15, 56)] among patients treated with SNT (p = 0.19). CONCLUSIONS: TNT ensures the delivery of intended systemic therapy prior to a complicated operation without decreasing the chance of successful surgery; a window of operability was not lost. Patients who can tolerate SNT will likely benefit from TNT.

Importance of Normalization of CA19-9 Levels Following Neoadjuvant Therapy in Patients With Localized Pancreatic Cancer.

OBJECTIVE: Carbohydrate antigen 19-9 (CA19-9) is a prognostic marker for patients with pancreatic cancer (PC), but its value as a treatment biomarker is unclear. SUMMARY BACKGROUND DATA: Although CA19-9 is an established prognostic marker for patients with PC, it is unclear how CA19-9 monitoring should be used to guide multimodality treatment and what level of change in CA19-9 constitutes a meaningful treatment response. METHODS: CA19-9 measurements at diagnosis (pretx), after completion of all planned neoadjuvant therapy (preop), and after surgery (postop) were analyzed in patients with localized PC who had an elevated CA19-9 (≥35 U/dL) at diagnosis. Patients were classified by: 1) quartiles of pretx CA19-9 (Q1-4); 2) proportional changes in CA19-9 (ΔCA19-9) after the completion of neoadjuvant therapy; 3) normalization (CA19-9 <35 U/dL) of preop CA19-9; and 4) normalization of postop CA19-9. RESULTS: Among 131 patients, the median overall survival (OS) was 30 months; 68 months for the 33 patients in Q1 of pretx CA19-9 (<80 U/dL) compared with 25 months for the 98 patients in Q2-4 (P = 0.03). For the 98 patients in Q2-4, preop CA19-9 declined (from pretx) in 86 (88%), but there was no association between the magnitude of ΔCA19-9 and OS (P = 0.77). Median OS of the 98 patients who did (n = 29) or did not (n = 69) normalize their preop CA19-9 were 46 and 23 months, respectively (P = 0.02). Of the 69 patients with an elevated preop CA19-9, 32 (46%) normalized their postop CA19-9. Failure to normalize preop or postop CA19-9 was associated with a 2.77-fold and 4.03-fold increased risk of death, respectively (P < 0.003) as compared with patients with normal preop CA19-9. CONCLUSIONS: Following neoadjuvant therapy, normalization of CA19-9, rather than the magnitude of change, is the strongest prognostic marker for long-term survival.

Radiation therapy for gynecologic malignancies during the COVID-19 pandemic: International expert consensus recommendations.

OBJECTIVE: To develop expert consensus recommendations regarding radiation therapy for gynecologic malignancies during the COVID-19 pandemic. METHODS: An international committee of ten experts in gynecologic radiation oncology convened to provide consensus recommendations for patients with gynecologic malignancies referred for radiation therapy. Treatment priority groups were established. A review of the relevant literature was performed and different clinical scenarios were categorized into three priority groups. For each stage and clinical scenario in cervical, endometrial, vulvar, vaginal and ovarian cancer, specific recommendations regarding dose, technique, and timing were provided by the panel. RESULTS: Expert review and discussion generated consensus recommendations to guide radiation oncologists treating gynecologic malignancies during the COVID-19 pandemic. Priority scales for cervical, endometrial, vulvar, vaginal, and ovarian cancers are presented. Both radical and palliative treatments are discussed. Management of COVID-19 positive patients is considered. Hypofractionated radiation therapy should be used when feasible and recommendations regarding radiation dose, timing, and technique have been provided for external beam and brachytherapy treatments. Concurrent chemotherapy may be limited in some countries, and consideration of radiation alone is recommended. CONCLUSIONS: The expert consensus recommendations provide guidance for delivering radiation therapy during the COVID-19 pandemic. Specific recommendations have been provided for common clinical scenarios encountered in gynecologic radiation oncology with a focus on strategies to reduce patient and staff exposure to COVID-19.

Detection of germline variants using expanded multigene panels in patients with localized pancreatic cancer.

BACKGROUND: Current guidelines recommend genetic testing for all patients with pancreatic cancer (PC). METHODS: Patients with localized PC who received neoadjuvant therapy between 2009 and 2018 were identified. Genetic consultation (including personal and family history of cancer), genetic testing, and variant data were abstracted. RESULTS: Of 510 patients identified, 163 (32%) underwent genetic counseling and genetic testing was performed in 127 (25%). Patients who underwent genetic testing were younger (median age: 63 vs. 67, p = 0.01). Multi-gene testing was performed in 114 (90%) of 127 patients, targeted gene testing was performed in 8 (6%), and not specified in 5 (4%). Of 127 patients who underwent genetic testing, 20 (16%) had pathogenic (P)/likely pathogenic (LP) variants, observed in ATM (n = 7/105,7%), CHEK2 (n = 3/98, 3%), BRCA1 (n = 2/117, 2%), BRCA2 (n = 2/122, 2%), PALB2 (n = 1/115, 1%), MUTYH (n = 1/98, 1%), CDKN2A (n = 1/94, 1%), STK11 (n = 1/97, 1%), NBN (n = 1/98, 1%), and MSH6 (n = 1/97, 1%). Of 20 patients with either a P/LP variant, nine (45%) had a prior cancer, three (15%) had a first-degree relative with PC, and six (30%) had an any-degree relative with PC. CONCLUSION: Pathogenic/likely pathogenic variants were identified in 16% of patients who underwent genetic testing, 60% of which occurred in the homologous recombination pathway.

A Phase II Clinical Trial of Molecular Profiled Neoadjuvant Therapy for Localized Pancreatic Ductal Adenocarcinoma.

OBJECTIVES: One facet of precision medicine is the use of tumor molecular profiling to guide chemotherapeutic selection. We conducted the first prospective clinical trial of molecular profiling to guide neoadjuvant therapy in patients with operable pancreatic ductal adenocarcinoma (PDAC). We hypothesized that more effective systemic therapy would prevent disease progression during neoadjuvant therapy and, therefore, allow more patients to undergo surgery. METHODS: In patients with resectable and borderline resectable (BLR) PDAC, molecular profiling consisted of immunocytochemical staining of pretreatment endoscopic ultrasound-guided fine needle aspiration tumor biopsies using 6 biomarkers. Neoadjuvant systemic therapy was selected based on the molecular profiling results. The primary endpoint was the completion of all intended neoadjuvant therapy and surgery. RESULTS: The trial enrolled 130 patients; 61 (47%) resectable and 69 (53%) BLR. Molecular profiling was reported within a median of 5 business days (IQR: 3). Of the 130 patient samples, 95 (73%) had adequate cellularity for molecular profiling and 92 (71%) patients received molecular profile-directed therapy. Of the 92 patients who had predictive profiling, 74 (80%) received fluoropyrimidine-based therapy and 18 (20%) received gemcitabine-based therapies. Of the 130 patients, 107 (82%) completed all intended neoadjuvant therapy and surgery; 56 (92%) of the 61 with resectable PDAC and 51 (74%) of 69 with BLR PDAC. CONCLUSIONS: We report the first prospective clinical trial that utilized molecular profiling to select neoadjuvant therapy in patients with operable PDAC. Such high resectability rates have not been observed in prior neoadjuvant trials, suggesting that molecular profiling may improve the efficacy of chemotherapy in these patients.

Neoadjuvant treatment sequencing adds value to the care of patients with operable pancreatic cancer.

Treatment sequencing for resectable pancreatic cancer remains controversial and there is lack of level one evidence comparing neoadjuvant versus adjuvant strategies. However, a comparison of the cost-effectiveness analysis of the treatment strategies may help to better define the healthcare value of each approach. This review will highlight the rationale for multimodality therapy in the treatment of pancreatic cancer, discuss the advantages and disadvantages of adjuvant therapy, and conceptualize the cost-effectiveness of a neoadjuvant approach with regard to healthcare value. J. Surg. Oncol. 2016;114:291-295. © 2016 Wiley Periodicals, Inc.

Venous thromboembolism prophylaxis during neoadjuvant therapy for resectable and borderline resectable pancreatic cancer-Is it indicated?

PURPOSE: To describe venous thromboembolism (VTE) rates in patients with pancreatic cancer (PC) during neoadjuvant therapy. METHODS: Factors associated with VTE were evaluated using multivariable logistic regression modeling in patients with resectable and BLR PC treated with neoadjuvant therapy between 2009 and 2014. RESULTS: Prevalent VTEs were detected in 13 (5%) of the 260 patients. Incident VTEs were detected in 26 patients (10%); 9 (8%) of the 109 resectable and 17 (11%) of the 151 BLR patients (P = 0.53). Of the 26 incident events, 9 (35%) were PEs, 9 (35%) were extremity DVTs, and 8 (31%) involved the SMV/PV. VTEs were catheter-related in 7 (27%) of the 26 patients. Rh(D) antigen positivity was associated with a decreased risk of incident VTE (OR:0.32, 95%CI:0.11-0.85, P = 0.02). Completion of neoadjuvant therapy to include surgery occurred in 176 (75%) of the 234 patients without incident VTE as compared to 14 (54%) of the 26 patients with incident VTE (P = 0.02). The median survival for all 260 patients was 24.3 months: 17.0 months versus 24.6 months for patients who did and did not develop incident VTE during neoadjuvant therapy (P = 0.11). CONCLUSIONS: Patients with localized PC who receive neoadjuvant therapy are at significant risk of VTE and thromboprophylaxis may be warranted. J. Surg. Oncol. 2016;114:581-586. © 2016 Wiley Periodicals, Inc.

NRG Oncology/RTOG 0921: A phase 2 study of postoperative intensity-modulated radiotherapy with concurrent cisplatin and bevacizumab followed by carboplatin and paclitaxel for patients with endometrial cancer.

BACKGROUND: The current study was conducted to assess acute and late adverse events (AEs), overall survival (OS), pelvic failure, regional failure, distant failure, and disease-free survival in a prospective phase 2 clinical trial of bevacizumab and pelvic intensity-modulated radiotherapy (IMRT) with chemotherapy in patients with high-risk endometrial cancer. METHODS: Patients underwent a hysterectomy and lymph node removal, and had ≥1 of the following high-risk factors: grade 3 carcinoma with >50% myometrial invasion, grade 2 or 3 disease with any cervical stromal invasion, or known extrauterine extension confined to the pelvis. Treatment included pelvic IMRT and concurrent cisplatin on days 1 and 29 of radiation and bevacizumab (at a dose of 5 mg/kg on days 1, 15, and 29 of radiation) followed by adjuvant carboplatin and paclitaxel for 4 cycles. The primary endpoint was grade ≥3 AEs occurring within the first 90 days (toxicity was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events [version 4.0]). RESULTS: A total of 34 patients were accrued from November 2009 through December 2011, 30 of whom were eligible and received study treatment. Seven of 30 patients (23.3%; 1-sided 95% confidence interval, 10.6%-36.0%) developed grade ≥3 treatment-related nonhematologic toxicities within 90 days; an additional 6 patients experienced grade ≥3 toxicities between 90 and 365 days after treatment. The 2-year OS rate was 96.7% and the disease-free survival rate was 79.1%. No patient developed a within-field pelvic failure and no patients with International Federation of Gynecology and Obstetrics stage I to IIIA disease developed disease recurrence after a median follow-up of 26 months. CONCLUSIONS: Postoperative bevacizumab added to chemotherapy and pelvic IMRT appears to be well tolerated and results in high OS rates at 2 years for patients with high-risk endometrial carcinoma.

Seeing is saving: the benefit of 3D imaging in gynecologic brachytherapy.

Despite a concerning decline in the use of brachytherapy over the past decade, no other therapy is able to deliver a very high dose of radiation into or near a tumor, with a rapid fall-off of dose to adjacent structures. Compared to traditional X-ray-based brachytherapy that relies on points, the use of CT and MR for 3D planning of gynecologic brachytherapy provides a much more accurate volume-based calculation of dose to an image-defined tumor and to the bladder, rectum, sigmoid, and other pelvic organs at risk (OAR) for radiation complications. The publication of standardized guidelines and an online contouring teaching atlas for performing 3D image-based brachytherapy has created a universal platform for communication and training. This has resulted in a uniform approach to using image-guided brachytherapy for treatment and an internationally accepted format for reporting clinical outcomes. Significant improvements in survival and reductions in toxicity have been reported with the addition of image guidance to increase dose to tumor and decrease dose to the critical OAR. Future improvements in individualizing patient treatments should include a more precise definition of the target. This will allow dose modulation based on the amount of residual disease visualized on images obtained at the time of brachytherapy.

Pre-treatment carbohydrate antigen 19-9 does not predict the response to neoadjuvant therapy in patients with localized pancreatic cancer.

BACKGROUND: The prognostic value of CA19-9 in patients with pancreatic cancer (PC) treated with neoadjuvant therapy has not been well described. METHODS: Pre-treatment CA19-9 levels (with concomitant normal bilirubin level) in patients with localized PC were categorized as normal (≤35), low (36-200), moderate (201-1000), or high (>1000). Post-treatment CA19-9 was measured after neoadjuvant therapy, prior to surgery. RESULTS: Pre-treatment CA19-9 levels were evaluable in 235 patients, levels were normal in 60 (25%) patients, low in 78 (33%) patients, moderate in 69 (29%) and high in 28 (12%). After neoadjuvant therapy, post-treatment CA19-9 normalized (≤ 35) in 40 (51%) of the patients in the low group, 14 (21%) of the moderate and 5 (19%) of the high group (P < 0.001). Of the 235 patients, 168 (71%) completed all intended therapy including a pancreatectomy; 44 (73%), 62 (79%), 46 (67%) and 16 (57%) of the normal, low, moderate and high groups (P = 0.10). Among these 168 patients, the median overall survival was 38.4, 43.6, 44.7, 27.2 and 26.4 months for normal, low, moderate and high CA19-9 groups (log rank P = 0.72). Among resected patients, an elevated pre-treatment CA19-9 was of little prognostic value; instead, it was the CA19-9 response to neoadjuvant therapy that was prognostic [hazard ratio (HR): 1.80, P = 0.02]. CONCLUSIONS: Among patients who completed neoadjuvant therapy and surgery, pre-treatment CA19-9 obtained at the time of diagnosis was not predictive of overall survival, but normalization of post-treatment CA19-9 in response to neoadjuvant therapy was highly prognostic.

Treatment planning for MR-guided SBRT of pancreatic tumors on a 1.5 T MR-Linac: A global consensus protocol.

Background and purpose: Treatment planning for MR-guided stereotactic body radiotherapy (SBRT) for pancreatic tumors can be challenging, leading to a wide variation of protocols and practices. This study aimed to harmonize treatment planning by developing a consensus planning protocol for MR-guided pancreas SBRT on a 1.5 T MR-Linac. Materials and methods: A consortium was founded of thirteen centers that treat pancreatic tumors on a 1.5 T MR-Linac. A phased planning exercise was conducted in which centers iteratively created treatment plans for two cases of pancreatic cancer. Each phase was followed by a meeting where the instructions for the next phase were determined. After three phases, a consensus protocol was reached. Results: In the benchmarking phase (phase I), substantial variation between the SBRT protocols became apparent (for example, the gross tumor volume (GTV) D99% ranged between 36.8 - 53.7 Gy for case 1, 22.6 - 35.5 Gy for case 2). The next phase involved planning according to the same basic dosimetric objectives, constraints, and planning margins (phase II), which led to a large degree of harmonization (GTV D99% range: 47.9-53.6 Gy for case 1, 33.9-36.6 Gy for case 2). In phase III, the final consensus protocol was formulated in a treatment planning system template and again used for treatment planning. This not only resulted in further dosimetric harmonization (GTV D99% range: 48.2-50.9 Gy for case 1, 33.5-36.0 Gy for case 2) but also in less variation of estimated treatment delivery times. Conclusion: A global consensus protocol has been developed for treatment planning for MR-guided pancreatic SBRT on a 1.5 T MR-Linac. Aside from harmonizing the large variation in the current clinical practice, this protocol can provide a starting point for centers that are planning to treat pancreatic tumors on MR-Linac systems.

Safety and Tolerability of Online Adaptive High-Field Magnetic Resonance-Guided Radiotherapy.

Importance: In 2018, the first online adaptive magnetic resonance (MR)-guided radiotherapy (MRgRT) system using a 1.5-T MR-equipped linear accelerator (1.5-T MR-Linac) was clinically introduced. This system enables online adaptive radiotherapy, in which the radiation plan is adapted to size and shape changes of targets at each treatment session based on daily MR-visualized anatomy. Objective: To evaluate safety, tolerability, and technical feasibility of treatment with a 1.5-T MR-Linac, specifically focusing on the subset of patients treated with an online adaptive strategy (ie, the adapt-to-shape [ATS] approach). Design, Setting, and Participants: This cohort study included adults with solid tumors treated with a 1.5-T MR-Linac enrolled in Multi Outcome Evaluation for Radiation Therapy Using the MR-Linac (MOMENTUM), a large prospective international study of MRgRT between February 2019 and October 2021. Included were adults with solid tumors treated with a 1.5-T MR-Linac. Data were collected in Canada, Denmark, The Netherlands, United Kingdom, and the US. Data were analyzed in August 2023. Exposure: All patients underwent MRgRT using a 1.5-T MR-Linac. Radiation prescriptions were consistent with institutional standards of care. Main Outcomes and Measures: Patterns of care, tolerability, and technical feasibility (ie, treatment completed as planned). Acute high-grade radiotherapy-related toxic effects (ie, grade 3 or higher toxic effects according to Common Terminology Criteria for Adverse Events version 5.0) occurring within the first 3 months after treatment delivery. Results: In total, 1793 treatment courses (1772 patients) were included (median patient age, 69 years [range, 22-91 years]; 1384 male [77.2%]). Among 41 different treatment sites, common sites were prostate (745 [41.6%]), metastatic lymph nodes (233 [13.0%]), and brain (189 [10.5%]). ATS was used in 1050 courses (58.6%). MRgRT was completed as planned in 1720 treatment courses (95.9%). Patient withdrawal caused 5 patients (0.3%) to discontinue treatment. The incidence of radiotherapy-related grade 3 toxic effects was 1.4% (95% CI, 0.9%-2.0%) in the entire cohort and 0.4% (95% CI, 0.1%-1.0%) in the subset of patients treated with ATS. There were no radiotherapy-related grade 4 or 5 toxic effects. Conclusions and Relevance: In this cohort study of patients treated on a 1.5-T MR-Linac, radiotherapy was safe and well tolerated. Online adaptation of the radiation plan at each treatment session to account for anatomic variations was associated with a low risk of acute grade 3 toxic effects.

Deep learning auto-segmentation on multi-sequence magnetic resonance images for upper abdominal organs.

Introduction: Multi-sequence multi-parameter MRIs are often used to define targets and/or organs at risk (OAR) in radiation therapy (RT) planning. Deep learning has so far focused on developing auto-segmentation models based on a single MRI sequence. The purpose of this work is to develop a multi-sequence deep learning based auto-segmentation (mS-DLAS) based on multi-sequence abdominal MRIs. Materials and methods: Using a previously developed 3DResUnet network, a mS-DLAS model using 4 T1 and T2 weighted MRI acquired during routine RT simulation for 71 cases with abdominal tumors was trained and tested. Strategies including data pre-processing, Z-normalization approach, and data augmentation were employed. Additional 2 sequence specific T1 weighted (T1-M) and T2 weighted (T2-M) models were trained to evaluate performance of sequence-specific DLAS. Performance of all models was quantitatively evaluated using 6 surface and volumetric accuracy metrics. Results: The developed DLAS models were able to generate reasonable contours of 12 upper abdomen organs within 21 seconds for each testing case. The 3D average values of dice similarity coefficient (DSC), mean distance to agreement (MDA mm), 95 percentile Hausdorff distance (HD95% mm), percent volume difference (PVD), surface DSC (sDSC), and relative added path length (rAPL mm/cc) over all organs were 0.87, 1.79, 7.43, -8.95, 0.82, and 12.25, respectively, for mS-DLAS model. Collectively, 71% of the auto-segmented contours by the three models had relatively high quality. Additionally, the obtained mS-DLAS successfully segmented 9 out of 16 MRI sequences that were not used in the model training. Conclusion: We have developed an MRI-based mS-DLAS model for auto-segmenting of upper abdominal organs on MRI. Multi-sequence segmentation is desirable in routine clinical practice of RT for accurate organ and target delineation, particularly for abdominal tumors. Our work will act as a stepping stone for acquiring fast and accurate segmentation on multi-contrast MRI and make way for MR only guided radiation therapy.