Femoral Fracture in Primary Soft-Tissue Sarcoma of the Thigh and Groin Treated with Intensity-Modulated Radiation Therapy: Observed versus Expected Risk.

PURPOSE: This study was designed to compare the observed risk of femoral fracture in primary soft-tissue sarcoma (STS) of the thigh/groin treated with intensity-modulated radiation therapy (IMRT) to expected risk calculated using the Princess Margaret Hospital (PMH) nomogram. METHODS: Expected femoral fracture risk was calculated by using the PMH nomogram. Cumulative risk of fracture was estimated by using Kaplan-Meier statistics. Prognostic factors were assessed with univariate and multivariate analysis using Cox's stepwise regression. RESULTS: Between February 2002 and December 2010, 92 consecutive eligible patients were assessed. Median follow-up was 73 months (106 months in surviving patients). IMRT was delivered preoperatively (50 Gy) in 13 (14%) patients and postoperatively in 79 (86%) patients (median dose, 63 Gy; range, 59.4-66.6 Gy). The observed crude risk of fractures was 6.5% compared with 25.6% expected risk from the nomogram; the cumulative risk of fracture using IMRT at 5 years was 6.7% (95% CI 2.8-16.0%). The median time to fracture was 23 months (range, 6.9-88.6). Significant predictors of fracture on univariate analysis were age ≥ 60 years (p = 0.03), tumor location in the anterior thigh (p = 0.008), and periosteal stripping to > 20 cm (p < 0.0001). On multivariate analysis, age ≥ 60 years and periosteal stripping > 20 cm retained significance (p = 0.04 and p = 0.009, respectively). CONCLUSIONS: In this study, the cumulative risk of femur fracture in patients treated with IMRT (6.7%) is less than the expected risk using the PMH nomogram (25.6%). Established predictors of femur fracture, such as gender, tumor size, and dose of RT, seem to have less impact on fracture risk when using IMRT.

Sociodemographic Disparities in the Receipt of Adjuvant Chemotherapy Among Patients With Resected Stage I-III Pancreatic Adenocarcinoma.

BACKGROUND: Adjuvant therapy for resected pancreatic adenocarcinoma was given a category 1 NCCN recommendation in 2000, yet many patients do not receive chemotherapy after definitive surgery. Whether sociodemographic disparities exist for receipt of adjuvant chemotherapy is poorly understood. METHODS: The National Cancer Database was used to identify patients diagnosed with nonmetastatic pancreatic adenocarcinoma who underwent definitive surgery from 2004 through 2015. Multivariable logistic regression defined the adjusted odds ratio (aOR) and associated 95% CI of receipt of adjuvant chemotherapy. Among patients receiving chemotherapy, multivariable logistic regression assessed the odds of treatment with multiagent chemotherapy. RESULTS: Among 18,463 patients, 11,288 (61.1%) received any adjuvant chemotherapy. Sociodemographic factors inversely associated with receipt of any adjuvant chemotherapy included uninsured status (aOR, 0.61; 95% CI, 0.50-0.74), Medicaid insurance (aOR, 0.66; 95% CI, 0.57-0.77), and lower income (P<.001 for all income levels compared with ≥$46,000). Black race (aOR, 0.72; 95% CI, 0.57-0.90) and female sex (aOR, 0.75; 95% CI, 0.65-0.86) were associated with lower odds of receiving multiagent chemotherapy. There was a statistically significant interaction term between black race and age/comorbidity status (P=.03), such that 26.4% of black versus 35.8% of nonblack young (aged ≤65 years) and healthy (Charlson-Deyo comorbidity score 0) patients received multiagent adjuvant chemotherapy (P=.006), whereas multiagent adjuvant chemotherapy rates were similar among patients who were not young and healthy (P=.15). CONCLUSIONS: In this nationally representative study, receipt of adjuvant chemotherapy appeared to be associated with sociodemographic characteristics, independent of clinical factors. Sociodemographic differences in receipt of adjuvant chemotherapy may represent a missed opportunity for improving outcomes and a driver of oncologic disparities.

Natural history of 'second' biochemical failure after salvage radiation therapy for prostate cancer: a multi-institution study.

OBJECTIVES: To describe the natural history of prostate cancer in men who experience a second biochemical recurrence (BCR) after salvage radiotherapy (SRT) after prostatectomy. PATIENTS AND METHODS: After undergoing SRT at one of two institutions between 1986 and 2013, 286 patients experienced a second BCR, defined as two rises in prostate-specific antigen (PSA) of ≥0.2 ng/mL above nadir. Event rates for distant metastasis (DM) or freedom from DM (FFDM), castration-resistant prostate cancer (CRPC), prostate cancer-specific survival (PCSS), and overall survival (OS) were estimated using the Kaplan-Meier method. Cox regression was used for comparative analyses. RESULTS: At a median of 6.1 years after second BCR, DM, CRPC, PCSS and OS rates were 41%, 27%, 83% and 73%, respectively. On multivariable analysis, interval to second BCR <1 year (hazard ratio [HR] 2.66, 95% confidence interval [CI] 1.71-4.14; P < 0.001], Gleason score 8-10 (HR 1.65, 95% CI 1.07-2.54; P = 0.022), and concurrent ADT during SRT (HR 1.76, 95% CI 1.08-2.88; P = 0.024) were associated with FFDM, while PCSS was associated with interval to second BCR <1 year (HR 3.00, 95% CI 1.69-5.32; P < 0.001) and concurrent ADT during SRT (HR 2.15, CI 1.13-4.08; P = 0.019). These risk factors were used to stratify patients into three groups, with 6-year FFDM rates of 71%, 59% and 33%, and PCSS rates of 89%, 79%, and 65%, respectively. CONCLUSION: Following second BCR after SRT, clinical progression is enriched in a subgroup of patients with prostate cancer, while others remain without DM for long intervals. Stratifying patients into risk groups using prognostic factors may aid counselling and future trial design.

Rectal radiation dose-reduction techniques in prostate cancer: a focus on the rectal spacer.

Prostate cancer is the most common cancer in men. External beam radiotherapy by a variety of methods is a standard treatment option with excellent disease control. However, acute and late rectal side effects remain a limiting concern in intensification of therapy in higher-risk patients and in efforts to reduce treatment burden in others. A number of techniques have emerged that allow for high-radiation dose delivery to the prostate with reduced risk of rectal toxicity, including image-guided intensity-modulated radiation therapy, endorectal balloons and various forms of rectal spacers. Image-guided radiation therapy, either intensity-modulated radiation therapy or stereotactic ablative radiation therapy, in conjunction with a rectal spacer, is an efficacious means to reduce acute and long-term rectal toxicity.

Review of treatment options for oligometastatic non-small cell lung cancer.

Our understanding of metastatic disease is constantly evolving. Although outcomes for patients with stage IV non-small cell lung cancer (NSCLC) are poor, aggressive/radical local intervention may be effective in a subset of patients with limited or "oligometastatic" disease. Here we review and compare the range of available treatment options that are specific to oligometastatic NSCLC, and discuss potential directions of future clinical research.

Motion analysis comparing surface imaging and diaphragm tracking on kV projections for deep inspiration breath hold (DIBH).

BACKGROUND: Surface-guided imaging (SGI) is increasingly utilized to monitor patient motion during deep inspiration breath hold (DIBH) in radiotherapy. Understanding the association between surface and internal motion is crucial for effective monitoring. PURPOSE: To investigate the relation between motion detected by SGI using surface-guided radiotherapy (SGRT) and internal motion measured through diaphragm tracking on kV projections acquired with DIBH for online CBCT. METHODS: Both SGI and kV were simultaneously acquired for ten patients over a total of 200 breath holds (BH). Diaphragm tracking was performed using second-degree polynomial curve fitting on the derivative images for each kV projection and high-pass filtering at 1/30 Hz to remove rotational effects. The superior-inferior (SI) and anterior-posterior (AP) motions of SGI were then compared to kV tracking using various statistical measures. RESULTS: The correlation (individuals' median: -0.07 to 0.73) was a suboptimal metric for the BH data. The median and 95th percentile absolute differences between SGI-SI and kV were 0.73 mm and 3.46 mm, respectively, during DIBH. For SGI-AP, the corresponding values were 0.55 mm and 2.80 mm. For inter-BH measurements, the contingency table based on a 3 mm threshold indicated surface/diaphragm motion agreement for SGI-SI/kV and SGI-AP/kV was 61 % and 56 %, respectively. CONCLUSION: Both intra- and inter-BH measurements indicated a limited association between surface and diaphragm motion, with certain constraints noted due to kV tracking and DIBH data. These findings warrant further investigation into the association between surface and internal motion.

Pelvic insufficiency fractures in patients with cervical and endometrial cancer treated with postoperative pelvic radiation.

OBJECTIVE: There is an increased awareness of pelvic insufficiency fractures (PIF) as a potential morbidity of pelvic radiotherapy (RT). The purpose of this study was to determine the incidence of PIF and assess prognostic factors, including intensity-modulated RT (IMRT), in gynecologic oncology patients treated with postoperative pelvic RT. METHODS: We performed a retrospective review of all patients with endometrial or cervical carcinoma who received postoperative pelvic RT at our institution during 2000-2008. Patients who received definitive or palliative RT were excluded. RESULTS: A total of 222 patients were identified, of whom 11 (5%) developed PIF at a median time of 11.5months (range, 5.5-87.3months) from RT completion. The 5-year actuarial rate was 5.1% (95% CI 3.3-6.9). In patients with osteoporosis, the 5-year rate was 15.6% compared with 2.9% for those without (P=0.01). Similarly, patients who were on prior hormone-replacement therapy (HRT) had a higher rate (14.8% vs 4.1%, P=0.009). The median body-mass index (BMI) for patients who developed PIF was significantly lower than those who didn't (25.9 vs 27.2, P=0.016). The rate of PIF was 4.9% whether patients received IMRT or conventional RT. CONCLUSIONS: The 5-year risk of PIF for postoperative pelvic RT in cervical and endometrial cancer is 5.1%. Women with history of osteoporosis, prior HRT, or low BMI need to be counseled about the risk of PIF. The use of IMRT did not decrease PIF, but further studies are needed to determine if a dose/volume relationship exists between RT and PIF.

Postoperative pelvic intensity-modulated radiotherapy and concurrent chemotherapy in intermediate- and high-risk cervical cancer.

OBJECTIVE: According to national surveys, the use of intensity-modulated radiation therapy (IMRT) in gynecologic cancers is on the rise, yet there is still some reluctance to adopt adjuvant IMRT as standard practice. The purpose of this study is to report a single-institution experience using postoperative pelvic IMRT with concurrent chemotherapy in intermediate- and high-risk early stage cervical cancer. METHODS: From 1/2004 to 12/2009, 34 patients underwent radical hysterectomy and pelvic lymph node dissection (28 median nodes were removed) for early stage cervical cancer. Median dose of postoperative pelvic IMRT was 50.4 Gy (range, 45-50.4). All patients received concurrent cisplatin. RESULTS: With a median follow-up of 44 months, 3 patients have recurred; 1 vaginal recurrence, 1 regional and distant, and 1 distant. The 3- and 5-year disease-free survival (DFS) was 91.2% (95% CI, 81.4-100%) and overall survival (OS) was 91.1% (95% CI, 81.3-100%). All failures and all deaths were in the high-risk group (n=3/26). There was 32.3% G3-4 hematologic toxicity, 2.9% acute G3 gastrointestinal toxicity, and no acute G3 or higher genitourinary toxicity. There were no chronic G3 or higher toxicities. CONCLUSIONS: Oncologic outcomes with postoperative IMRT were very good, with DFS and OS rates of >90% at median follow-up of 44 months, despite a preponderance (76.5%) of high-risk features. Toxicity was minimal even in the setting of an aggressive trimodality approach. Data from this study and emerging data from the Phase II RTOG study (0418) demonstrate the advantages of postoperative IMRT in early stage cervical cancer.

Organ sparing treatment for penile cancer using a 3D-printed high-dose-rate brachytherapy applicator.

PURPOSE: We present a case study of the treatment of localized squamous cell carcinoma on the glans penis with a custom-fabricated high-dose-rate (HDR) brachytherapy applicator. METHODS AND MATERIALS: A cylindrically shaped applicator was fabricated with eight embedded channels suitable for standard plastic brachytherapy catheters. An additional custom silicone bolus/sleeve was designed to be used with the 3D-printed applicator to provide an additional offset from the source to skin to reduce the surface dose and for patient comfort. RESULTS: The patient (recurrent cT1a penile cancer) underwent CT simulation, and the brachytherapy plan was created with a nominal prescription dose of 40 Gy in 10 fractions given bidaily to the surface, and 35 Gy at 5 mm depth. Dose coverage to the clinical target volume was 94% (D90). Most fractions were treated with only 5-10 min of setup time. Follow up visits up to 1 year showed no evidence of disease with no significant changes in urinary and sexual function and limited cosmetic detriment to the patient. CONCLUSIONS: Patient-specific organ-sparing HDR plesiotherapy using 3D printing technology can provide reliable and reproducible patient setup and may be effective in achieving disease control for superficial penile cancer, although preserving patient quality of life.

Quality Metric to Assess Adequacy of Hydrogel Rectal Spacer Placement for Prostate Radiation Therapy and Association of Metric Score With Rectal Toxicity Outcomes.

Purpose: Although hydrogel spacer placement (HSP) minimizes rectal dose during prostate cancer radiation therapy, its potential benefit for modulating rectal toxicity could depend on the achieved prostate-rectal separation. We therefore developed a quality metric associated with rectal dose reduction and late rectal toxicity among patients treated with prostate stereotactic body radiation therapy (SBRT). Methods and Materials: A quality metric consisting of prostate-rectal interspace measurements from axial T2-weighted magnetic resonance imaging simulation images was applied to 42 men enrolled in a multi-institutional phase 2 study using HSP with prostate SBRT (45 Gy in 5 fractions). A score of 0, 1, or 2 was assigned to a prostate-rectal interspace measurement of <0.3 cm, 0.3 to 0.9 cm, or ≥1 cm, respectively. An overall spacer quality score (SQS) was computed from individual scores at rectal midline and ±1 cm laterally, located at the prostate base, midgland, and apex. Associations of SQS with rectal dosimetry and late toxicity were evaluated. Results: The majority of the analyzed cohort had an SQS of 1 (n = 17; 41%) or 2 (n = 18; 43%). SQS was associated with maximum rectal point dose (rectal Dmax; P = .002), maximum dose to 1 cc of rectum (D1cc; P = .004), and volume of rectum receiving ≥100% of prescription dose (V45; P = .046) and ≥40 Gy (V40; P = .005). SQS was also associated with a higher incidence of (P = .01) and highest-graded late rectal toxicity (P = .01). Among the 20 men who developed late grade ≥1 rectal toxicity, 57%, 71%, and 22% had an SQS of 0, 1, and 2, respectively. Men with an SQS of 0 or 1 compared with 2 had 4.67-fold (95% CI, 0.72-30.11) or 8.40-fold (95% CI, 1.83-38.57) greater odds, respectively, of developing late rectal toxicity. Conclusions: We developed a reliable and informative metric for assessing HSP, which appears to be associated with rectal dosimetry and late rectal toxicity after prostate SBRT.

Thermal ablation compared to stereotactic body radiation therapy for hepatocellular carcinoma: A multicenter retrospective comparative study.

BACKGROUND AIMS: Early-stage HCC can be treated with thermal ablation or stereotactic body radiation therapy (SBRT). We retrospectively compared local progression, mortality, and toxicity among patients with HCC treated with ablation or SBRT in a multicenter, US cohort. APPROACH RESULTS: We included adult patients with treatment-naïve HCC lesions without vascular invasion treated with thermal ablation or SBRT per individual physician or institutional preference from January 2012 to December 2018. Outcomes included local progression after a 3-month landmark period assessed at the lesion level and overall survival at the patient level. Inverse probability of treatment weighting was used to account for imbalances in treatment groups. The Cox proportional hazard modeling was used to compare progression and overall survival, and logistic regression was used for toxicity. There were 642 patients with 786 lesions (median size: 2.1 cm) treated with ablation or SBRT. In adjusted analyses, SBRT was associated with a reduced risk of local progression compared to ablation (aHR 0.30, 95% CI: 0.15-0.60). However, SBRT-treated patients had an increased risk of liver dysfunction at 3 months (absolute difference 5.5%, aOR 2.31, 95% CI: 1.13-4.73) and death (aHR 2.04, 95% CI: 1.44-2.88, p < 0.0001). CONCLUSIONS: In this multicenter study of patients with HCC, SBRT was associated with a lower risk of local progression compared to thermal ablation but higher all-cause mortality. Survival differences may be attributable to residual confounding, patient selection, or downstream treatments. These retrospective real-world data help guide treatment decisions while demonstrating the need for a prospective clinical trial.

Brachial Plexus Tolerance to Single-Session SABR in a Pig Model.

PURPOSE: The single-session dose tolerance of the spinal nerves has been observed to be similar to that of the spinal cord in pigs, counter to the perception that peripheral nerves are more tolerant to radiation. This pilot study aims to obtain a first impression of the single-session dose-response of the brachial plexus using pigs as a model. METHODS AND MATERIALS: Ten Yucatan minipigs underwent computed tomography and magnetic resonance imaging for treatment planning, followed by single-session stereotactic ablative radiotherapy. A 2.5-cm length of the left-sided brachial plexus cords was irradiated. Pigs were distributed in 3 groups with prescription doses of 16 (n = 3), 19 (n = 4), and 22 Gy (n = 3). Neurologic status was assessed by observation for changes in gait and electrodiagnostic examination. Histopathologic examination was performed with light microscopy of paraffin-embedded sections stained with Luxol fast blue/periodic acid-Schiff and Masson's trichrome. RESULTS: Seven of the 10 pigs developed motor deficit to the front limb of the irradiated side, with a latency from 5 to 8 weeks after irradiation. Probit analysis of the maximum nerve dose yields an estimated ED50 of 19.3 Gy for neurologic deficit, but the number of animals was insufficient to estimate 95% confidence intervals. No motor deficits were observed at a maximum dose of 17.6 Gy for any pig. Nerve conduction studies showed an absence of sensory response in all responders and absent or low motor response in most of the responders (71%). All symptomatic pigs showed histologic lesions to the left-sided plexus consistent with radiation-induced neuropathy. CONCLUSIONS: The single-session ED50 for symptomatic plexopathy in Yucatan minipigs after irradiation of a 2.5-cm length of the brachial plexus cords was determined to be 19.3 Gy. The dose-response curve overlaps that of the spinal nerves and the spinal cord in the same animal model. The relationship between the brachial plexus tolerance in pigs and humans is unknown, and caution is warranted when extrapolating for clinical use.

Dose-Intensified Stereotactic Ablative Radiation for Localized Prostate Cancer.

Purpose: Stereotactic ablative radiation (SAbR) has been increasingly used in prostate cancer (PCa) given its convenience and cost efficacy. Optimal doses remain poorly defined with limited prospective comparative trials and long-term safety/efficacy data at higher dose levels. We analyzed toxicity and outcomes for SAbR in men with localized PCa at escalated 45 Gy in 5 fractions. Methods and Materials: This study retrospectively analyzed men from 2015 to 2019 with PCa who received linear-accelerator-based SAbR to 45 Gy in 5 fractions, along with perirectal hydrogel spacer, fiducial placement, and MRI-based planning. Disease control outcomes were calculated from end of treatment. Minimally important difference (MID) assessing patient-reported quality of life was defined as greater than a one-half standard deviation increase in American Urological Association (AUA) symptom score after SAbR. Results: Two-hundred and forty-nine (249) low-, intermediate-, and high-risk PCa patients with median follow-up of 14.9 months for clinical toxicity were included. Acute urinary grade II toxicity occurred in 20.4% of patients. Acute grade II GI toxicity occurred in 7.3% of patients. For follow-up > 2 years (n = 69), late GU and GI grade ≥III toxicity occurred in 5.8% and 1.5% of patients, respectively. MID was evident in 31.8%, 23.4%, 35.8%, 37.0%, 33.3%, and 26.7% of patients at 3, 6, 12, 24, 36, and 48 months, respectively. The median follow-up for biochemical recurrence was 22.6 months with biochemical failure-free survival of 100% at 1 year (n = 226) and 98.7% for years 2 (n = 113) and 3 (n = 54). Conclusions: SAbR for PCa at 45 Gy in 5 fractions shows an encouraging safety profile. Prospective studies with longer follow-up are warranted to establish this dose regimen as standard of care for PCa.

Ablative Radiation Therapy in Oligometastatic Pancreatic Cancer to Delay Polyprogression, Limit Chemotherapy, and Improve Outcomes.

PURPOSE: The oligometastatic state is observed in patients across many malignancies, with increased recognition regarding improved outcomes after local therapies. However, there is limited data specifically regarding pancreatic ductal adenocarcinoma. We hypothesized that an oligometastatic pancreatic ductal adenocarcinoma (OPanc) phenotype would benefit from stereotactic ablative radiation therapy (SABR) to all active metastatic sites. Here, we report our institutional experience of SABR-treated OPanc to evaluate the feasibility of the approach. METHODS AND MATERIALS: A retrospective review of patients with synchronous or metachronous OPanc (1 to 5 metastases) who received SABR to all active metastatic sites was performed. We identified a comparable group of patients with similar metastatic burden, range of CA19-9 levels, and no progression for at least 5 months who did not receive SABR. We compared overall survival as the primary outcome, and polyprogression-free survival and time off chemotherapy as the secondary exploratory assessments. A third group presenting with stage IV pancreatic ductal adenocarcinoma and more than 5 distant lesions (polymetastatic) was identified to help define expected outcomes after polyprogression. RESULTS: Our study included 20 patients with OPanc receiving SABR and 21 who did not. SABR was delivered to 38 metastatic tumors. Out of the 20 SABR-treated OPanc patients, 17 (85%) had 6 or more months of time off chemotherapy, compared with 7 patients (33.3%) among the chemotherapy-treated group. Median polyprogression-free survival was 40 and 14 months (hazard ratio = 0.2; 95% confidence interval, 0.07-0.54; P = .0009), and overall survival was 42 and 18 months (hazard ratio = 0.21; 95% confidence interval, 0.08-0.53; P = .0003), for SABR- and chemotherapy-treated cohorts, respectively. CONCLUSIONS: Management of OPanc with SABR as local regional therapy could improve outcomes in a selected population and warrants prospective evaluation.

SABR for High-Risk Prostate Cancer: A Prospective Multilevel MRI-Based Dose Escalation Trial.

PURPOSE: Radiation dose intensification improves outcome in men with high-risk prostate cancer (HR-PCa). A prospective trial was conducted to determine safety, feasibility, and maximal tolerated dose of multilevel magnetic resonance imaging (MRI)-based 5-fraction SABR in patients with HR-PCa. METHODS AND MATERIALS: This phase I clinical trial enrolled patients with HR-PCa with grade group ≥4, prostate-specific antigen (PSA) ≥20 ng/mL, or radiographic ≥T3, and well-defined prostatic lesions on multiparametric MRI (mpMRI) into 4 dose-escalation cohorts. The initial cohort received 47.5 Gy to the prostate, 50 Gy to mpMRI-defined intraprostatic lesion(s), and 22.5 Gy to pelvic lymph nodes in 5 fractions. Radiation doses were escalated for pelvic nodes to 25 Gy and mpMRI lesion(s) to 52.5 Gy and then 55 Gy. Escalation was performed sequentially according to rule-based trial design with 7 to 15 patients per cohort and a 90-day observation period. All men received peri-rectal hydrogel spacer, intraprostatic fiducial placement, and 2 years of androgen deprivation. The primary endpoint was maximal tolerated dose according to a 90-day acute dose-limiting toxicity (DLT) rate <33%. DLT was defined as National Cancer Institute Common Toxicity Criteria for Adverse Events ≥grade 3 treatment-related toxicity. Secondary outcomes included acute and delayed gastrointestinal (GI)/genitourinary (GU) toxicity graded with Common Toxicity Criteria for Adverse Events. RESULTS: Fifty-five of the 62 enrolled patients were included in the analysis. Dose was escalated through all 4 cohorts without observing any DLTs. Median overall follow-up was 18 months, with a median follow-up of 42, 24, 12, and 7.5 months for cohorts 1 to 4 respectively. Acute and late grade 2 GU toxicities were 25% and 20%, while GI were 13% and 7%, respectively. Late grade 3 GU and GI toxicities were 2% and 0%, respectively. CONCLUSIONS: SABR dose for HR-PCa was safely escalated with multilevel dose painting of 47.5 Gy to prostate, 55 Gy to mpMRI-defined intraprostatic lesions, and 25 Gy to pelvic nodal region in 5 fractions. Longer and ongoing follow-up will be required to assess late toxicity.

Automatic liver tumor localization using deep learning-based liver boundary motion estimation and biomechanical modeling (DL-Bio).

PURPOSE: Recently, two-dimensional-to-three-dimensional (2D-3D) deformable registration has been applied to deform liver tumor contours from prior reference images onto estimated cone-beam computed tomography (CBCT) target images to automate on-board tumor localizations. Biomechanical modeling has also been introduced to fine-tune the intra-liver deformation-vector-fields (DVFs) solved by 2D-3D deformable registration, especially at low-contrast regions, using tissue elasticity information and liver boundary DVFs. However, the caudal liver boundary shows low contrast from surrounding tissues in the cone-beam projections, which degrades the accuracy of the intensity-based 2D-3D deformable registration there and results in less accurate boundary conditions for biomechanical modeling. We developed a deep-learning (DL)-based method to optimize the liver boundary DVFs after 2D-3D deformable registration to further improve the accuracy of subsequent biomechanical modeling and liver tumor localization. METHODS: The DL-based network was built based on the U-Net architecture. The network was trained in a supervised fashion to learn motion correlation between cranial and caudal liver boundaries to optimize the liver boundary DVFs. Inputs of the network had three channels, and each channel featured the 3D DVFs estimated by the 2D-3D deformable registration along one Cartesian direction (x, y, z). To incorporate patient-specific liver boundary information into the DVFs, the DVFs were masked by a liver boundary ring structure generated from the liver contour of the prior reference image. The network outputs were the optimized DVFs along the liver boundary with higher accuracy. From these optimized DVFs, boundary conditions were extracted for biomechanical modeling to further optimize the solution of intra-liver tumor motion. We evaluated the method using 34 liver cancer patient cases, with 24 for training and 10 for testing. We evaluated and compared the performance of three methods: 2D-3D deformable registration, 2D-3D-Bio (2D-3D deformable registration with biomechanical modeling), and DL-Bio (DL model prediction with biomechanical modeling). The tumor localization errors were quantified through calculating the center-of-mass-errors (COMEs), DICE coefficients, and Hausdorff distance between deformed liver tumor contours and manually segmented "gold-standard" contours. RESULTS: The predicted DVFs by the DL model showed improved accuracy at the liver boundary, which translated into more accurate liver tumor localizations through biomechanical modeling. On a total of 90 evaluated images and tumor contours, the average (± sd) liver tumor COMEs of the 2D-3D, 2D-3D-Bio, and DL-Bio techniques were 4.7 ± 1.9 mm, 2.9 ± 1.0 mm, and 1.7 ± 0.4 mm. The corresponding average (± sd) DICE coefficients were 0.60 ± 0.12, 0.71 ± 0.07, and 0.78 ± 0.03; and the average (± sd) Hausdorff distances were 7.0 ± 2.6 mm, 5.4 ± 1.5 mm, and 4.5 ± 1.3 mm, respectively. CONCLUSION: DL-Bio solves a general correlation model to improve the accuracy of the DVFs at the liver boundary. With improved boundary conditions, the accuracy of biomechanical modeling can be further increased for accurate intra-liver low-contrast tumor localization.

Trends and Factors Associated With Receipt of Upfront Surgery for Stage II to III Rectal Adenocarcinoma in the United States, 2006 to 2016.

INTRODUCTION: The German rectal study published in 2004 established neoadjuvant chemoradiation as a standard of care for locally advanced rectal cancer and current National Comprehensive Cancer Network guidelines endorse several preoperative regimens. Upfront surgery, however, is considered substandard care. In the era of evolving treatment paradigms for locally advanced rectal cancer, we sought to assess trends and predictors of receipt of upfront surgery for stage II to III rectal cancer. METHODS: The National Cancer Database was used to identify patients diagnosed with clinical stage II to III rectal adenocarcinoma between 2006 and 2016. Multivariable logistic regression defined adjusted odds ratios and associated 95% confidence intervals of receipt of upfront definitive surgery. The timing of upfront surgery relative to day of diagnosis and rate of receipt of adjuvant therapy were also estimated. RESULTS: Among 51,562 patients, 6411 (12.4%) were treated with upfront surgery, which decreased from 16.7% in 2006 to 7.1% in 2016 (P<0.001). The majority of patients (5737 [89.5%]) had definitive surgery after initial diagnostic biopsy. Variables associated with receipt of upfront surgery included female sex, older age, higher comorbidity score, and treatment at a community cancer center (P<0.001). Among those receiving upfront surgery, 2904 (45.3%) received adjuvant radiation therapy, 3218 (50.2%) received adjuvant chemotherapy, and 2559 (39.9%) received no further treatment. CONCLUSIONS: The proportion of patients with clinical stage II to III rectal cancer treated with upfront surgery has steadily declined since 2006, however, certain subgroups appear to remain at greater risk. Further research is needed to better elucidate patient and systems-level factors contributing to these disparities in care.

Review of brachytherapy complications - Upper gastrointestinal tract.

While brachytherapy applications are not widely used for cancer diagnoses in the upper GI tract (including the esophagus, liver, stomach, and pancreas), they have a clear role in palliation and symptom management and occasionally definitive locoregional treatment. With the increasing use of image-guided techniques, the incidence of side effects and complications has shown to be lower than many other alternative treatment modalities, making brachytherapy approaches a preferred treatment option. This review examines procedural complications and acute and chronic adverse effects from radiation associated with esophageal, hepatobiliary, and pancreatic brachytherapy and their management.

Exploratory ensemble interpretable model for predicting local failure in head and neck cancer: the additive benefit of CT and intra-treatment cone-beam computed tomography features.

BACKGROUND: Local failure (LF) following chemoradiation (CRT) for head and neck cancer is associated with poor overall survival. If machine learning techniques could stratify patients at risk of treatment failure based on baseline and intra-treatment imaging, such a model could facilitate response-adapted approaches to escalate, de-escalate, or switch therapy. METHODS: A 1:2 retrospective case control cohort of patients treated at a single institution with definitive radiotherapy for head and neck cancer who failed locally, in-field at a primary or nodal structure were included. Radiomic features were extracted from baseline CT and CBCT scans at fractions 1 and 21 (delta) of radiotherapy with PyRadiomics and were selected for by: reproducibility (intra-class correlation coefficients ≥0.95), redundancy [maximum relevance and minimum redundancy (mRMR)], and informativeness [recursive feature elimination (RFE)]. Separate models predicting LF of primaries or nodes were created using the explainable boosting machine (EBM) classifier with 5-fold cross-validation for (I) clinical only, (II) radiomic only (CT1 and delta features), and (III) fused models (clinical + radiomic). Twenty-five iterations were performed, and predicted scores were averaged with a parallel ensemble design. Receiver operating characteristic curves were compared between models with paired-samples t-tests. RESULTS: The fused ensemble model for primaries (using clinical, CT1, and delta features) achieved an AUC of 0.871 with a sensitivity of 78.3% and specificity of 90.9% at the maximum Youden J statistic. The fused ensemble model trended towards improvement when compared to the clinical only ensemble model (AUC =0.788, P=0.134) but reached significance when compared to the radiomic ensemble model (AUC =0.770, P=0.017). The fused ensemble model for nodes achieved an AUC of 0.910 with a sensitivity of 100.0% and specificity of 68.0%, which also trended towards improvement when compared to the clinical model (AUC =0.865, P=0.080). CONCLUSIONS: The fused ensemble EBM model achieved high discriminatory ability at predicting LF for head and neck cancer in independent primary and nodal structures. Although an additive benefit of delta radiomics over clinical factors could not be proven, the results trended towards improvement with the fused ensemble model, which are promising and worthy of prospective investigation in a larger cohort.

A systematic review of intraluminal high dose rate brachytherapy in the management of malignant biliary tract obstruction and cholangiocarcinoma.

PURPOSE: To conduct a systematic review evaluating the impact of high dose rate (HDR) intraluminal brachytherapy (ILBT) in the management of malignant biliary obstruction and cholangiocarcinoma with specific focus on stent patency, clinical outcomes and toxicities. METHODS AND MATERIALS: A review of published articles was conducted using Medline, Embase and Cochrane databases using the search terms "bile duct carcinoma" or "cholangiocarcinoma" or "bile duct neoplasms" in combination with "brachytherapy" or "high dose rate brachytherapy" or "HDR brachytherapy". Studies published in English and reporting outcomes of ≥10 patients were included in the review. Only the most recent experience was included if same patients were included in sequential publications. RESULTS: Seventeen studies were identified that met the inclusion criteria. Significant heterogeneity was observed in treatment regimens, which included use of surgery, external beam radiation (EBRT), and/or intra-arterial and intravenous chemotherapy in conjunction with ILBT. Nevertheless, among the included studies, use of ILBT appeared to result in longer duration of stent patency: 10 months with ILBT compared to 4-6 months without ILBT. A trend was observed towards prolonged local control and improved complete and partial response rates in patients treated with ILBT with or without EBRT. Weighted mean overall survival of patients treated with ILBT alone was 11.8 months compared to 10.5 months for those that received EBRT +/- chemotherapy in addition to ILBT. The included studies reported low complication rates and toxicity related to ILBT. CONCLUSION: Brachytherapy can be an effective and safe tool in the management of malignant biliary tract obstruction in combination with stenting. Both retrospective and prospective studies have suggested improved outcomes when HDR ILBT is combined with percutaneous stenting.